Multiple myeloma (MM), a malignant plasma cell disorder, continues to pose major treatment challenges for patients with relapsed or refractory disease (R/R MM), despite continuous advances in therapeutic options. While CAR-T cell therapies targeting B-cell maturation antigen (BCMA) have achieved objective response rates (ORR) of 73%–100%, resistance mechanisms such as antigen heterogeneity and BCMA loss often lead to disease progression. This underscores the urgent need for new targets and more effective therapies.
G protein-coupled receptor class C group 5 member D (GPRC5D), an orphan transmembrane receptor, is widely expressed in malignant plasma cells but limited in normal tissues such as plasma cells and hair follicles. Its expression is independent of BCMA, making it an ideal novel target. Previous CAR-T studies targeting GPRC5D demonstrated encouraging safety and efficacy but were limited by expression dependency and lengthy manufacturing times.
Against this background, Professor Du Juan’s team initiated a first-in-human, single-center, single-arm Phase I clinical trial of CT071, a GPRC5D-targeted CAR-T therapy, to evaluate its preliminary efficacy, safety, and cellular kinetics in patients with R/R MM. The findings were published in The Lancet Haematology.
A Chinese Innovation for Refractory Myeloma
23 adult patients diagnosed with R/R MM or plasma cell leukemia were enrolled in the study per International Myeloma Working Group (IMWG) criteria. Twenty patients received CT071 infusion. Eligible participants had an ECOG performance score of 0–2 and had undergone at least three prior lines of therapy (including a proteasome inhibitor and an immunomodulatory drug) or were refractory to both.
Among the 20 treated patients, the median age was 63 years (IQR 53.0–65.5), with 60% male. They had received a median of five prior therapy lines; 95% were dual-drug refractory, 65% triple-drug refractory, and 25% penta-drug refractory. Half (50%) had undergone autologous stem cell transplantation (Auto-HSCT), and 25% relapsed after anti-BCMA or dual BCMA/CD19 CAR-T therapy. Additionally, 20% presented with extramedullary disease, and 70% had at least one high-risk cytogenetic abnormality — indicating a heavily pretreated, high-risk population.
Rapid Manufacturing Platform
CT071 was manufactured using the CARcelerate platform, which shortens the production process to approximately 30 hours, significantly reducing vein-to-vein time while yielding younger T cells. Patients underwent leukapheresis for autologous PBMC collection, followed by T-cell isolation, activation, transduction, and formulation. Prior to infusion, patients received lymphodepleting chemotherapy with fludarabine (30 mg/m²/day) and cyclophosphamide (300 mg/m²/day) for three consecutive days. CT071 was infused on Day 0 at adjustable rates depending on infusion-related reactions.
The initial dose level was 0.1×10⁶ CAR-T cells/kg, with planned escalation to 0.3×10⁶ and 0.6×10⁶ cells/kg based on safety, pharmacokinetics, and preliminary efficacy.
Outstanding Efficacy and Manageable Safety Profile
Efficacy: 100% Objective Response Rate with Deep Remission
At a median follow-up of 10.71 months, all patients achieved an objective response (ORR 100%; 95% CI, 83.2–100.0).
- 50% (10 patients) achieved stringent complete response (sCR),
- 50% (10 patients) achieved partial response (PR).
In the 0.1×10⁶ cells/kg cohort (9 patients), 67% reached CR/sCR with a median time to CR or better of 1.0 month. In the 0.3×10⁶ cells/kg cohort (11 patients), 36% achieved CR/sCR, with a median time of 1.9 months.
Notably, all 5 patients previously treated with anti-BCMA CAR-T responded to CT071 — 2 achieved PR, 1 VGPR, and 2 sCR.
Moreover, 90% (18/20) achieved MRD negativity (10⁻⁶ sensitivity by multicolor flow cytometry), including 93% (13/14) with high-risk cytogenetics. The median time to MRD negativity was 29 days, suggesting CT071 may overcome poor prognostic factors.
Cellular Kinetics: Strong Expansion and Sustained Persistence
CAR-T cell expansion was observed in all patients, with a median peak of 24,103 copies/μg gDNA and a median persistence of 98 days.
- In the 0.1×10⁶ group: median persistence 59 days
- In the 0.3×10⁶ group: median persistence 182 days
Only 1 patient tested positive for anti-drug antibodies by week 4.
Safety: Well Tolerated with Controllable Adverse Events
No dose-limiting toxicities were observed, and the recommended Phase II dose was established at 0.1×10⁶ CAR-T cells/kg.
All patients experienced hematologic adverse events (AEs).
- 60% (12/20) experienced cytokine release syndrome (CRS), all Grade 1–2, median onset 9 days, median duration 3 days, managed effectively with tocilizumab and/or corticosteroids.
- One patient (5%) experienced Grade 3 ICANS, which improved after corticosteroid treatment.
- Common non-hematologic AEs included hypokalemia (80%), elevated interleukin levels (35%), and increased LDH (30%). Four patients experienced Grade 1 nail shedding and one had mild rash; all recovered after symptomatic treatment.
- No treatment-related deaths occurred.
A Breakthrough in Myeloma Therapy — Expanding the Possibilities
CT071, a fully human, autologous, second-generation GPRC5D-targeted CAR-T therapy, demonstrated exceptional efficacy and a favorable safety profile, even among patients relapsed after prior anti-BCMA CAR-T therapy. This breakthrough offers a new therapeutic option for heavily pretreated and high-risk R/R MM patients.
The CARcelerate platform’s ultra-rapid manufacturing (≈30 hours) and short median vein-to-vein time (25 days) significantly reduce disease progression risk during waiting periods and minimize the need for bridging therapy — enhancing accessibility and timeliness.
Unlike previous GPRC5D CAR-T studies (e.g., OriCAR-017, which required ≥20% GPRC5D expression), CT071 efficacy was independent of baseline GPRC5D expression, broadening its potential clinical applicability.
A multicenter Phase II trial is now underway to further evaluate CT071’s efficacy and safety in R/R and newly diagnosed high-risk MM. With ongoing research, CT071 is poised to reshape the treatment landscape for multiple myeloma and bring renewed hope to patients worldwide.
