Promising Safety and Efficacy of Trovocabtagene Autoleucel (C-CAR088) Followed ASCT in Ultra High-Risk Multiple Myeloma (UHR-MM) Patients
Authors: Xu Yan , Li Wensi , An Gang , Sui Weiwei , Deng Shuhui , Wang Tingyu , Yi Shuhua , Wang Qi , Lyu Rui , Wenjie Xiong , Du Chenxing , Liu Wei , Huang Wenyang , Zhu Judy , Huang Jiaqi , Zheng Chengxiao , Lan Liping , Zhu Kevin , Qiu Lugui , Zou Dehui 
Published: December 2024

Background:

Although the overall survival of multiple myeloma (MM) has improved significantly, patients with ultra-high-risk features (UHR-MM) had dismal outcomes. New therapies to address this unmet medical need are warranted.

Trovocabtagene autoleucel (trovo-cel, C-CAR088), an anti-BCMA CAR T-cell manufactured by Shanghai AbelZeta Ltd., demonstrated good efficacy and safety profile in patients with relapsed or refractory multiple myeloma (R/R MM) [1]. Hereby, we report the results of a phase I study of trovo-cel followed ASCT in UHR-MM patients (NCT05632380).

Methods:

UHR-MM are defined as: 1) Genetic ultra-high risk: del(17p)≥60%; or ≥2 high-risk cytogenetic abnormalities including TP53 mutation, del(17p)/P53 deletion, t(4;14), t(14;16), t(14;20), 1q21 gain/ amplification, and &lt;CR after 4 cycles standard first-line therapy; 2) Primary refractory: &lt;MR after 2 cycles or &lt;PR after 4 cycles standard first-line therapy; 3) Early relapse: disease progression within 6 months from the standard first-line therapy; 4) primary plasma cell leukemia (PCL) history and &lt; CR after 4 cycles standard first-line therapy. Standard first-line therapy should be standard triplet-based regimen including at least one PI, one IMIDs, and glucocorticoid. Prior ASCT or CAR-T treatment are excluded.

Patients undergo conditioning (melphalan alone or in combine with fludarabine) followed by ASCT on Day 0 and trovo-cel single intravenous infusion on Day 3. IMIDs based maintenance is allowed after 3 months post ASCT per investigator's decision.

Results:

As of April 10th, 2024, 12 UHR-MM patients completed ASCT followed by trovo-cel infusion. Seven patients received melphalan and 5 received fludarabine combining melphalan conditioning. Trovo-cel was administrated at 3 × 106 cells/kg for all 12 patients.

The median age was 56 years (range: 39-69) and 10 (83.3%) were male. With median 1 (range: 1-2) previous line of therapy, the median disease course is 9.85 months. Nine patients (75%) had received daratumumab, with six had been treated with dara-based quadruplet or quintuplet therapy. Two patients (16.7%) had genetic ultra-high risk features, six patients (50%) were primary refractory, two (16.7%) were early relapse, and four patients (33.3%) had primary PCL history, two patients met more than 1 UHR definition. One (8.3%) patients had extramedullary disease. Nine patients (75%) received bridging and 11 received maintenance therapy.

With a median follow-up of 9.5 months (from ASCT date), 11 patients (91.7%) had experienced CRS and fully recovered, one developed grade 2 CRS, other events all were grade 1. No ICANS event was reported. As expected, AEs are dominated by hematological toxicities. All 12 patients achieved hematopoietic reconstitution within 3 months after ASCT, and 11 completed hematopoietic reconstitution within 28 days after ASCT, with a median time of 17 days for ANC reconstitution (≥0.5×109/L) and 14 days for PLT reconstitution (≥20×109/L) post ASCT.

By cutoff date, one patient died from pneumonia at 8 months post ASCT, which was considered not related to trovo-cel; one patient progressed at 9 months post ASCT and died from progression after withdrawal of the study. Ten patients are under follow-up.

The ORR was 100%, with 11 patients reached sCR (91.7%), 1 VGPR (8.3%). All sCR patients are MRD negative. To date, two patients maintained response until 18 months post ASCT, and four patients maintained response until 12 months post ASCT. The median DOR, PFS and OS were not reached by cutoff date.

Robust CAR T-cell expansion was observed, with a median Tmax of 7 days (range 4~8). The median Cmax was 806,109 copies/μg gDNA, and the median AUC0~28day was 6,986,578 copies/μg gDNA.day. The pharmacokinetic profile is similar to that of trovo-cel in R/RMM patients, but with an earlier peak of CAR-T expansion.

Conclusion:

Trovol-cel followed ASCT demonstrated promising deep and durable response and was well tolerated in UHR-MM patients. CRS events are slight, hematopoietic reconstruction rate was 100%. We are looking forward to more patients gaining long-term benefit from this new treatment.

[1] Qu X, An G, Sui W, et al. Phase 1 study of C-CAR088, a novel humanized anti-BCMA CAR T-cell therapy in relapsed/ refractory multiple myeloma. Journal for ImmunoTherapy of Cancer 2022;10:e005145.