Phase 1 study of CART-ddBCMA in relapsed or refractory multiple myeloma.
Authors: Frigault Matthew J. , Rosenblatt Jacalyn , Cook Daniella , Cho Ha Na , Depinho Gabriel D. , Logan Emma , Liegel Jessica , Prabhakar Yougeesh , Cornwell Christine , Banerjee Kamalika , Rotte Anand , Heery Christopher Ryan , Avigan David , Jakubowiak Andrzej J. , Bishop Michael Russell 
Published: June 2022

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Background: Chimeric Antigen Receptor (CAR) T cell therapies targeting B-cell maturation antigen (BCMA) have demonstrated benefit in patients (pts) with relapsed and/or refractory Multiple Myeloma (RRMM). CART-ddBCMA is an autologous anti-BCMA CAR T cell therapy that utilizes a novel, synthetic binding domain, called a D-Domain, instead of a typical scFv binder. The objective of this first-in-human trial is to assess the safety and efficacy of CART-ddBCMA. Methods: This is a Phase 1, multi-center, open label, dose escalation trial for pts with RRMM who have received ≥3 prior regimens or are triple-refractory. After apheresis, bridging therapy is allowed during manufacturing. Pts receive fludarabine and cyclophosphamide (30/300 mg/m2/day) days -5 to -3 and CART-ddBCMA infusion on day 0. Dose escalation was performed at 100 (DL1) and 300 (DL2) x 106 (± 20%) CAR+T cells, followed by expansion of DL1. The primary endpoint is incidence of adverse events (AEs), including dose-limiting toxicities (DLTs). Additional endpoints are depth and duration of response (IMWG Criteria), minimal residual disease (MRD, clonoSEQ), progression-free (PFS) and overall survival (OS). Pts with 1- and 3-months follow-up were eligible for safety and efficacy analysis, respectively. Results: As of January 25, 2022, 25 pts received CART-ddBCMA, with median age 66 (range: 44-76), after a median of 5 prior lines of therapy (3-16), including 10 (40%) with extramedullary disease (EMD). Median follow-up was 9.8 (2-23.7) months. Overall, 25 pts (19 DL1; 6 DL2) were evaluable for safety and 24 (18 DL1; 6 DL2) for efficacy analysis. All pts experienced CRS, but only 1 pt (in DL2) had grade (gr) 3 CRS. All other CRS cases were gr ≤2, with no cases of gr ≥3 CRS in DL1. Four pts experienced ICANS (2, gr ≤2; 2, gr 3), with 1 gr 3 case in each of DL1 (5%) and DL2 (17%). Standard management resulted in resolution of CRS/ICANS within 30 days in all cases without sequelae. The ORR = 100%, sCR/CR rate = 67%, and ≥VGPR rate = 88%. Conversion to CR/sCR has occurred with longer follow-up, as late as month 9 in this trial. At time of data-cut 5 pts in DL1 with PR/VGPR have < 9 months follow-up, with 4 (of 4 evaluable) negative at ≥10-5 for MRD. Overall, 17 of 20 (85%) evaluable pts have achieved best MRD response of ≥10-5. In the dose escalation pts (i.e., those with longest follow-up, n = 12), the ORR and CR/sCR rate was 100% and 75%, respectively, despite 58% (7/12) EMD in this group. Of the first 6 pts dosed in DL1, 4 (67%) continue in ongoing sCR beyond 18 months, including 3 with EMD. Median duration of response, PFS and OS were not evaluable at the time of data-cut because 19 of 24 evaluable pts (79%) remain in ongoing response. Conclusions: CART-ddBCMA administration, to date, has demonstrated clinical activity, including 100% ORR with rates of CR/sCR and ≥VGPR of 67% and 88%, respectively. Durable responses beyond 18 months have been observed, including in pts with EMD. Clinical trial information: NCT04155749.