Concurrent CAR T Product Infusion Appears Feasible in R/R Multiple Myeloma

Concurrently infusing anti-GPRC5D agent MCARH109 and anti-BCMA therapy MCARH125 showed feasibility without excessive toxicities among patients with relapsed/refractory multiple myeloma, according to a presentation on data from the phase 1 TANDEMM trial (NCT04555551) at the 22nd Annual International Myeloma Society Meeting and Exposition.

At dose level 0, the BCMA-directed therapy alone produced 3 stringent complete responses (sCRs) and 5 very good partial responses (VGPRs) among 6 evaluable patients; 1 patient converted from a VGPR to an sCR during therapy. Combination therapy at dose level 1 showed 1 sCR among 3 evaluable patients who all received prior BCMA-directed agents. Additionally, there were 4 VGPRs and 1 other PR among 6 evaluable patients who received dose level 2, which included 3 who received prior BCMA-directed treatment.

The median progression-free survival (PFS) among those who received dose level 0 was 20.1 months (95% CI, 15.5-not reached [NR]). At dose levels 1 and 2, the median PFS was 18.2 months (95% CI, 6.4-NR; P = .21).

“The co-infusion of 2 CAR [chimeric antigen receptor] T products concurrently is feasible and was not associated with excessive toxicities. In a heavily pretreated patient population, the co-infusion approach was associated with high, durable responses. Relapses after co-infusion can be associated with downregulation of 1 or both antigens,” presenting study author Saad Z. Usmani, MD, MBA, FACP, FASCO, a hematologist-oncologist specializing in the care of patients with multiple myeloma and other plasma cell disorders at Memorial Sloan Kettering Cancer Center, stated in the presentation. “Baseline T cell factors are associated with refractoriness and early relapse…. Optimal strategy for targeting BCMA and GPRC5D is unknown; co-infusion vs a single CAR-targeting both antigens vs bispecific or trispecific antibodies are being explored.”

According to the study authors, CAR T-cell therapies targeting BCMA and GPRC5D yield deep responses, yet relapses are still common. Usmani highlighted how plasma cell-related, T cell-related, and disease microenvironment-related factors can contribute to resistance towards different immune therapies. Additionally, antigen loss may occur following CAR T-cell therapy, regardless of whether BCMA or GPRC5D is the target.

Investigators designed the TANDEMM study to determine whether they could overcome the aforementioned antigen loss by targeting GPRC5D and BCMA simultaneously. The trial included a 3+3 dose-escalation design encompassing 3 cohorts. One cohort received 150 x 10⁶ cells of the BCMA therapy alone (n = 6); another received 50 x 10⁶ and 150 x 10⁶ cells of GPRC5D and BCMA therapy, respectively (n = 3); and the last cohort received 150 x 10⁶ cells of both types of therapy (n = 6).

The study’s primary end point was the safety of concurrent infusion. Secondary end points included efficacy as well as MCARH125 and MCARH109 expansion and persistence.

Those with at least 3 prior lines of treatment and previous treatment encompassing a proteasome inhibitor, immunomodulatory drug, and CD38 antibody were eligible for enrollment on the trial. The trial also allowed patients with previous BCMA-based treatment, CAR T-cell therapy, and allogeneic stem cell transplant to enroll. Those with nonsecretory myeloma were also permitted to enroll.

Among 17 evaluable patients, the median age was 64 years (range, 51-73), and most patients were male (80%). Most patients also had high-risk cytogenetics (80%), penta-exposed disease (87%), and prior autologous transplant (87%).

The most common toxicities among patients who received anti-BCMA therapy alone included cytokine release syndrome (CRS; n = 6), anemia (n = 4), and thrombocytopenia (n = 3). Grade 3/4 toxicities in this cohort included neutropenia (n = 5), thrombocytopenia (n = 2), anemia (n = 1), infections (n = 1), and macrophage activation syndrome (n = 1).

Among patients who received concurrent infusion therapy, the most frequent any-grade adverse effects included CRS (n = 9), nail changes (n = 5), infections (n = 4), and anemia (n = 4). Grade 3/4 toxicities in this group consisted of neutropenia (n = 9), thrombocytopenia (n = 5), anemia (n = 5), infections (n = 2), and macrophage activation syndrome (n = 1).

Reference

Mailankody S, Mitra S, Herrera K, et al. Concurrent administration of BCMA and GPRC5D chimeric antigen receptor (CAR) T cells for the treatment of relapsed or refractory multiple myeloma: results from the phase I TANDEMM clinical trial. Presented at the 22nd Annual International Myeloma Society Meeting and Exposition; September 17-20, 2025; Toronto, Canada. Abstract OA-71.