Novel GPRC5D-Directed CAR T-Cell Therapy Produces Durable Remissions in R/R Myeloma

RD118, a novel, fully human anti-GPRC5D chimeric antigen receptor (CAR) T-cell therapy, generated an overall response rate (ORR) of 94.4% and a manageable safety profile in patients with heavily pretreated relapsed/refractory multiple myeloma, including those who had previously progressed on BCMA-directed CAR T-cell therapy, according to data from a phase 1 dose-escalation trial and its expansion study (NCT05759793; NCT05219721) published in Blood.^1-3

Findings showed that at a median follow-up of 17.0 months, RD118 induced a complete response (CR) or stringent CR (sCR) rate of 72.2% in evaluable patients (n = 18), and a median progression-free survival (PFS) of 18.2 months (95% CI, 14.4-not estimable).¹ The 12-month PFS and overall survival (OS) rates were 82.1% and 93.3%, respectively. Notably, among patients who had previously received BCMA-directed CAR T-cell therapy (n = 7), the ORR was 85.7%, including a CR/sCR rate of 71.4%.

What distinguishes RD118 from other GPRC5D-targeted CAR T-cell therapies?

RD118 is engineered with a fully human nanobody (VHH) as its antigen-binding domain. Compared with conventional single-chain variable fragments used in other investigational GPRC5D-directed CAR T-cell therapies, the nanobody format offers a smaller molecular size, reduced immunogenicity, and potentially enhanced in vivo persistence. The construct also incorporates a 4-1BB costimulatory domain and a CD3ζ activation domain to support robust CAR T-cell expansion and sustained antitumor activity.¹

In this first-in-human phase 1 study conducted at 2 sites in China, 18 patients with relapsed/refractory multiple myeloma (n = 17) or primary plasma cell leukemia (pPCL; n = 1) received a single infusion of RD118 following lymphodepletion with fludarabine and cyclophosphamide. Three dose levels of RD118 were evaluated: 1.0 × 10⁶, 2.0 × 10⁶, and 3.0 × 10⁶ CAR+ T cells/kg.¹

Who were the patients enrolled in the study?

The cohort included patients with a median age of 59.5 years who received a median of 5 prior lines of therapy (range, 3-8). Notably, 50% of patients had double-hit cytogenetics, 50% had triple-class refractory disease, and 22.2% had penta-refractory disease. Prior BCMA-targeted CAR T-cell therapy had been received by 38.9% of patients. Additional prior treatments included autologous stem cell transplantation (38.9%), daratumumab (Darzalex; 77.8%), proteasome inhibitors (100%), and immunomodulatory drugs (100%). Extramedullary disease was reported in 16.7% of patients.¹

What were the other key efficacy findings?

As of April 20, 2025, the data cutoff, all 11 CAR T-cell therapy–naive patients had responded, with 72.7% achieving CR/sCR. The median time to first response was 29 days, and the median time to CR was 189 days.¹

Minimal residual disease (MRD) negativity at a sensitivity of 10⁻⁵ was achieved by day 28 in 88.2% of responders, including 90.9% of CAR T-cell therapy–naive patients. Among all 18 infused patients, the MRD negativity rate was 83.3%. The median duration of response (DOR) was 16.4 months (95% CI, 13.5-not reached).

In the ultra–high-risk subgroups, 8 of 9 patients with double-hit cytogenetics responded, with a median DOR of 16.4 months. All 3 patients with extramedullary disease and the 1 patient with pPCL achieved sCR and remained in remission at data cutoff.

What was the safety profile of RD118?

All 18 patients experienced at least 1 adverse event, most commonly hematologic toxicities. Grade 3 or 4 neutropenia and thrombocytopenia were common but resolved to grade 2 or lower within 2 and 3 months post infusion, respectively.¹

Cytokine release syndrome (CRS) occurred in 88.9% of patients, but was predominantly grade 1 or 2 (72.2% grade 1; 11.1% grade 2). One patient in the high-dose cohort experienced grade 4 CRS complicated by disseminated intravascular coagulation and acute kidney injury—the only dose-limiting toxicity—which resolved with intensive management including tocilizumab (Actemra), corticosteroids, ruxolitinib (Jakafi), and renal replacement therapy. One 71-year-old patient in the middle-dose group developed grade 3 immune effector cell–associated neurotoxicity syndrome (ICANS) on day +10, which resolved completely by day +12 following corticosteroid intervention. No cerebellar toxicities or treatment-related deaths occurred.¹

Off-target toxicities consistent with GPRC5D expression in keratinized tissues were observed: grade 1 nail changes (44.4%), grade 2 rash (16.7%), pruritus (16.7%), and mild alopecia (11.1%). Rash and pruritus were managed effectively with oral corticosteroids or antihistamines. Investigators note that the absence of cerebellar toxicity, which has been observed with some other GPRC5D-directed therapies, may be attributable to the unique fully human nanobody design of RD118.¹

References

1. Pan M, Wang D, Xu J, et al. The fully human anti-GPRC5D CAR T-cell therapy RD118 induces durable remissions in relapsed/refractory multiple myeloma. Blood. 2026;147(5):513-519. doi:10.1182/blood.2025030559
2. Safety and efficacy of anti-GPRC5D CAR-T cells therapy in the treatment of R/R MM. ClinicalTrials.gov. Updated April 20, 2023. Accessed May 26, 2026. https://clinicaltrials.gov/study/NCT05749133
3. A study of CAR-GPRC5D in patients with relapsed/​refractory multiple myeloma or plasma cell leukemia. ClinicalTrials.gov. Updated June 11, 2025. Accessed May 26, 2026. https://clinicaltrials.gov/study/NCT05219721