麻豆传媒

Use of an allogeneic B-cell maturation antigen (BCMA)-targeting CAR T-cell therapy was feasible and safe and induced responses in patients with relapsed or refractory multiple myeloma, according to interim results from the phase I .

Among 43 patients who were treated with escalating doses of the agent (ALLO-715) after lymphodepletion with a regimen containing an investigational anti-CD52 antibody (ALLO-647), investigators found that cytokine release syndrome (CRS) and neurologic toxicity rates of ALLO-715 compared favorably with those seen with commercially available autologous anti-BCMA products.

As for the study's secondary endpoints, the overall response rate (ORR) was 56%, with about a third achieving a very good partial response (VGPR) or better, reported Sham Mailankody, MBBS, of Memorial Sloan Cancer Center in New York City, and colleagues in .

That rate increased to 71% in the group treated at the optimal cell dose of 320 × 10⁶ CAR T cells after an intensified conditioning regimen incorporating fludarabine, cyclophosphamide, and ALLO-647.

"ALLO-715 is the first allogeneic CAR T-cell therapy for myeloma and these initial results from the UNIVERSAL trial provide evidence of feasibility, safety and efficacy for this off-the-shelf cellular therapy as a potential treatment for patients with multiple myeloma," wrote Mailankody and colleagues.

Their study included 48 adults (median age 64, 63% male) with relapsed or refractory multiple myeloma who had received at least three prior lines of therapy, had an ECOG performance status of 0 or 1, and adequate organ function. Participants had a median time of 4.9 years from diagnosis and a median of five previous treatment regimens.

Most of the patients (43 of 48) received lymphodepletion with an ALLO-647-based regimen: fludarabine (90 mg/m²) and cyclophosphamide (900 mg/m²) combined with ALLO-647 at a 3-day dose of 39 mg (FCA39), 60 mg (FCA60), or 90 mg (FCA90), or the combination of cyclophosphamide and ALLO-647 without fludarabine.

Safety and Efficacy

Grade ≥3 adverse events (AEs) were reported in 88.0% patients who received the treatment. The most frequent AEs were neutropenia (69.8%), anemia (55.8%), and thrombocytopenia (51.2%). Of 10 deaths that occurred during the study after ALLO-715 administration, seven were related to disease progression, while three were instances of grade 5 infections including fungal pneumonia, adenoviral hepatitis, and sepsis.

CRS was observed in 24 patients (55.8%), with one grade ≥3 event (2.3%), and neurotoxicity in six patients (14%), with no grade ≥3 events, "which is somewhat lower than the rates seen with with autologous anti-BCMA CAR T cell therapy," the authors observed.

Regarding efficacy, at a median follow-up of 1o.2 months, 24 patients had a response (56%), with 15 (34.9%) experiencing a VGPR or better. Most responses were seen at the highest dose levels (19 of 27 at the 320 × 10⁶ dose, and three of six at the 480 × 10⁶ dose).

Across the different ALLO-647-containing, lymphodepleting regimens tested, the most responses occurred with the fludarabine-, cyclophosphamide-, and ALLO-647-based regimens at the 320 × 10⁶ dose level, with 17 of 24 patients (70.8%) achieving a response, including 11 (45.8%) with a VGPR and six (25%) with a complete or stringent complete response.

The median time to response for this cohort was 16 days, and the median duration of response was 8.3 months.

Mailankody and his colleagues noted that among 10 patients treated with the FCA60 lymphodepletion regimen at a dose level of 320 × 10⁶, their 80% ORR "falls in the range of those observed with other anti-BCMA therapies in a relapsed/refractory [multiple myeloma] setting."

In a , Jennifer Brudno, MD, and James Kochenderfer, MD, both of the National Cancer Institute, said the future use of ALLO-715 should be considered in the context of other off-the-shelf BCMA targeting therapies, such as the bispecific T-cell engager teclistamab (Tecvayli). They noted teclistamab appeared to have a , but with greater durability, and with comparable CRS and toxicity rates in a phase I-II trial.

"In a scenario in which an off-the-shelf CAR T-cell therapy is available in addition to teclistamab, choices would need to be tailored to an individual patient's treatment goals and preference for an upfront cellular therapy versus a continuously administered drug therapy," they wrote.

Comment