A Prospective Investigator-Initiated Phase 1/2 Study of BCMA/CD19 Dual-Targeting CAR T Therapy in Patients with Relapsed/Refractory Multiple Myeloma Including Those with Extramedullary Disease

Background

KQ-2003 is a BCMA/CD19 dual-targeting CAR T-cell therapy product, utilizing the latest parallel CAR structure to enhance the cell activity and persistence, and the dual CAR structure alleviate the antigen evasion of single target therapy. This prospective Investigator-Initiated study (NCT04714827) in China aims to evaluate the safety, tolerability, and preliminary efficacy of KQ-2003 CAR-T cells in patients (pts) with relapsed/refractory multiple myeloma (RRMM), particularly in those with extramedullary disease (EMD). Furthermore, the phase 1/2a KQ-2003-CAR-T IND study (NCT06223646) in RRMM is already ongoing in China.

Method

This prospective, multi-center, open label, dose escalation trial enrolls RRMM pts with ≥1 prior lines of therapy including proteasome inhibitor (PI), and immunomodulatory drug (IMiDs), and/or anti-CD38. Pts received lymphodepletion with fludarabine (30 mg/m²/day) and cyclophosphamide (300 mg/m²/day) on days -5 to -3, and then a single intravenous infusion of KQ-2003 CAR-T cells (day 0) in three dose levels (DL) based on a standard 3+3 design: DL1, DL2, or DL3 (1.0, 2.0, or 3.0×10⁶ CAR+ cells/kg). The objective was to evaluate the safety, tolerability, preliminary efficacy and PK/PD characteristics, and to determine the maximum tolerated dose (MTD), dose limiting toxicity (DLT). Hematological response was assessed per IMWG criteria and minimal residual disease (MRD) by new generation flow (NGF). EMD was assessed per Proposal Refinement PET Response Criteria.

Results

As of the Jul.25,2024 clinical cutoff, 23 pts (52.2% male; median age 64 (range 52-77) ) with RRMM received KQ-2003 (3 DL1, 11 DL2 and 9 DL3). The median follow-up duration was 13.7 mo (range 2.1-35.2). Pts had received a median of 5 prior lines of therapy (range 2-11). 91.3% (21/23) were triple-refractory, and 26.1% (6/23) penta-refractory. 65.2%(15/23) had high-risk/ultrahigh-risk cytogenetic profile.

60.9% (14/23) of pts had EMD at baseline, including 7 extramedullary extraosseous (EM-E), 5 extramedullary-bone related (EM-B), 2 pts with both.

In the EMD group, 5 pts (5/14, 35.7%) have no hematological measurable indicators, and the response was evaluated by PET-CT.

Hematological overall response rate (ORR) was 100.0% (18/18), with a sCR/CR rate of 88.9% (16/18), VGPR rate of 11.1% (2/18). The median time to first response was 1.2 mo (N=18, range 0.6–3.1; 22.2% ≤1.0 mo), and the median time to CR/sCR was 2.7 mo (N=16, range 0.6–9.1; 50.0% ≤3.0 mo). Of 19 MRD-evaluable pts, 100% were MRD-negative (10^-5), and the 6-mo and 12-mo MRD-neg rate were 80.0%(8/10) and 100.0%(3/3), respectively.

The PET ORR of EMD pts was 85.7%(12/14), including 64.3%(9/14) complete metabolic response (CMR), 21.4% (3/14) partial metabolic response (PMR) and 14.3% (2/14) stable metabolic disease (SMD). 64.3% (9/14) and 50.0% (7/14) of EMD pts had > 50% and > 75% reduction in the size of soft tissue plasmacytomas, respectively. In the 5 EMD pts without hematological measurable indicators, the PET ORR was 80% (4/5) (2 CMR, 2 PMR and 1 SMD).

The median duration of response (DOR) was not reached (NR). The 6-mo progression-free survival (PFS) and overall survival (OS) rates were 86.5% (73.4–100) and 86.2% (72.8–100), 12-mo PFS and OS rates were 75.3% (58.4–97.0) and 86.2% (72.8–100) respectively. The median PFS and OS were NR.

Totally 4 deaths occurred, including 2 on study and assessed as therapy-related (both severe pneumonia), and 2 deaths for PD.

CRS and ICANS were respectively seen in 21/23 (91.3%, grade 3/4 4.3%), and 5/23 (21.7%, grade 3/4 8.7%). The median time to CRS onset was 5d (range 1–9) with a median duration of 4d (range 1–15). The median time to ICANS onset was 10 d (range 8–23) with a median duration of 3d (range 1–9). No DLTs were observed.

KQ-2003 CAR+ T cells copy number (VCN) showed the median Tmax was 14.0, 11.5, and 9.0 d in DL1, DL2 and DL3, respectively. The median Cmax was 140.6, 168.2, and 83.9 copies/ug DNA with long duration of persistence. Among pts with 6 and 12 mo’ follow-up, 66.7% (10/15) and 62.5% (5/8) had detectable CAR+ T cells in peripheral blood.

Conclusions

BCMA/CD19 dual-targeting CAR-T KQ-2003 showed early, deep and durable response in RRMM with acceptable safety. More importantly, it exerted promising efficacy in EMD pts, including the clinical intractable EM-E, which merits further investigation.