In four patients with relapsed/refractory multiple myeloma, the investigational, in vivo, BCMA-directed CAR-T therapy–generating agent KLN-1010 was associated with deep, ongoing minimal residual disease (MRD)–negative responses, and the treatment had a favorable safety profile as an off-the-shelf product, clinical trial data have shown.
First-in-human results from the phase 1 inMMyCAR trial were presented during the 2025 ASH Annual Meeting.
Responses deepened over time, with patient 1 achieving a complete response at a MRD sensitivity level of 10-6 after month 5; patient 2 achieving a partial response (PR) at a MRD sensitivity level of 10-5 during month 4; patient 3 achieving a PR at a MRD sensitivity level of 10-5 during month 3; and patient 4 achieving a PR at a MRD sensitivity level of 10-5 at the beginning of month 2. Of note, in the first two patients with the longest follow-up, MRD-negative bone marrow responses were sustained through three months.
Glossary
Minimal residual disease (MRD): A very small number of cancer cells that remain in the body after treatment. These cells are too few to cause symptoms but can be detected with sensitive tests.
Complete response: All signs of cancer disappear after treatment. This does not always mean the cancer is cured, but no cancer can be found on tests.
Partial response: The cancer shrinks but does not go away completely.
Immune effector cell–associated neurotoxicity syndrome (ICANS): A temporary side effect that can occur after immune-based therapies (like CAR-T cells). It can cause confusion, trouble speaking, headaches or drowsiness.
Cytokine release syndrome (CRS): A reaction that happens when the immune system becomes very active during certain cancer treatments. It may cause fever, low blood pressure, or trouble breathing.
Infusion-related reaction (IRR): Symptoms such as fever, chills, rash or low blood pressure that can occur during or shortly after a medicine is given by infusion.
Lymphocytosis: A higher-than-normal number of lymphocytes (a type of white blood cell). Sometimes this happens as part of the body’s response to treatment.
Lymphopenia: A lower-than-normal number of lymphocytes, which may increase the risk of infection.
Neutropenia: A low level of neutrophils (another type of white blood cell), which increases infection risk.
Febrile neutropenia: A fever that occurs when neutrophil levels are very low. This is considered an emergency because it can signal a serious infection.
Anemia: A low red blood cell count. This can cause tiredness, shortness of breath, or dizziness.
Thrombocytopenia: A low platelet count. Platelets are needed for blood clotting, so low levels may lead to easy bruising or bleeding.
Hypomagnesemia: Low magnesium levels in the blood. This may cause muscle cramps, weakness, or abnormal heart rhythms.
Hypokalemia: Low potassium levels in the blood. Symptoms may include fatigue, muscle weakness, or irregular heartbeat.
Vasovagal syncope: A brief fainting episode caused by a sudden drop in heart rate and blood pressure, often triggered by pain, stress, or medical procedures.
CAR-T cell expansion occurred despite the absence of lymphodepleting chemotherapy. All patients experienced a rise in lymphocyte count. Dexamethasone was administered to patients 3 and 4 with prompt resolution and no clinical sequelae. Additionally, CAR-positive T cells were detected in the blood at day 15 at rates of 35%, 22%, 72% and 85%, and comprised a mixture of CD4 and CD8 CAR T-cells. Of note, the highest level of CAR-positive cells was achieved at dose level –1.
“These initial MRD-negative responses and persistent CAR-T cell [expansion may be] prognostic of ongoing clinical responses,” presenting author Phoebe Joy Ho, a professor at the University of Sydney, shared. “Establishing durability of response [DOR] remains a priority in continued follow-up, and updated results will be presented at future meetings.”
Ho is also a senior staff specialist in hematology, the director of research, and head of the Multiple Myeloma Research Unit and Thalassemia/Haemoglobinopathy Unit at the Institute of Haematology, Royal Prince Alfred Hospital in Sydney, Australia.
Why was KLN-1010 chosen for investigation in this patient population, and what makes its mechanism of action unique?
KLN‑1010 is an envelope-modified, replication-incompetent, self-inactivating modified lentiviral vector gene therapy administered intravenously to generate novel, fully-human anti-BCMA CAR-T cells in vivo. Designed as an off-the-shelf therapy, KLN-1010 eliminates the need for preconditioning lymphodepleting chemotherapy, simplifies the logistics of CAR-T cell administration, and may increase T-cell fitness through the absence of ex vivo culture, all of which could improve access to CAR-T cell therapies, Ho explained.
How was this phase 1 trial designed?
inMMyCAR is a first-in-human, dose-escalation/-expansion study conducted at three different sites in Australia: Peter MacCallum Cancer Center, The Alfred Hospital and Royal Prince Alfred Hospital. The study plans to enroll approximately 20 patients with relapsed/refractory multiple myeloma who received three or more lines of prior therapy, including a proteasome inhibitor (PI), immunomodulatory drug (IMiD) or anti-CD38 antibodies. Other eligibility criteria include an ECOG performance status of 0 or 1 and adequate bone marrow or organ function.
The ages of patients 1, 2, 3 and 4 were 72 years, 62 years, 61 years and 70 years, respectively. Patients 1 and 4 were male; patients 2 and 3 were female. These patients received 4, 3, 3 and 5 prior lines of therapy, respectively. Patients 1, 3, and 4 were all refractory to PIs, IMiDs, and anti-CD38 antibodies; patient 2 was only refractory to IMiDs and anti-CD38 antibodies. No patients had extramedullary disease and all patients had previously undergone autologous stem cell transplant.
What should be known about the agent’s safety profile?
Investigators did not observe any instances of immune effector cell–associated neurotoxicity syndrome or delayed neurotoxicity. Moreover, all cases of cytokine release syndrome (CRS) were low-grade, and CRS events were consistent with those seen with ex vivo CAR-T cell therapies. The median onset of CRS was 10 days, and the median duration was 5.5 days. Two Grade 1 (mild)/2 (moderate) CRS events occurred at dose level 1, and 1 grade 1/2 CRS event occurred at dose level –1. Dexamethasone and Actemra (tocilizumab) were administered as supportive care measures (three patients each).
Treatment-emergent side effects that occurred in more than one patient included Infusion-related reactions (IRR; grade 1/2, two patients; grade 3 (severe) or higher, one patient [dose-limiting toxicity]), lymphocytosis (one patient each), hypomagnesemia (two and zero patients), and hypokalemia (two and zero patients). Grade 3 or higher treatment-emergent side effects included febrile neutropenia, IRR, lymphopenia, lymphocytosis, anemia, vasovagal syncope and pneumonia (one patient each).
Cytopenias were also minimal, with only one case of grade 4 (life-threatening) transient neutropenia reported. Grade 3 or higher anemia and thrombocytopenia occurred in one patient each on study days 15 and 16, respectively, and lasted for two days. Two patients experienced grade 3 or higher neutropenia. One grade 1/2 and one grade 3 or higher IRR occurred at dose level 1; tocilizumab and steroids were administered as supportive care. One grade 1/2 IRR occurred at dose level –1, and paracetamol was administered as supportive care.
This favorable safety and tolerability profile, which was achieved with an off-the-shelf product, suggests that outpatient administration of KLN-1010 may be feasible, Ho concluded.
References
- “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: results of a phase 2 trial” by Phoebe Joy Ho et al., Blood.
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