Sequencing T-cell redirection therapies leads to deep and durable responses in patients with relapsed/refractory myeloma

Abstract

T-cell redirection therapy with chimeric antigen receptor (CAR)-T cells and bispecific antibodies (BiAbs) has shown promising efficacy in heavily pretreated relapsed/refractory multiple myeloma (RRMM) patients, leading to the approval of two CAR-T cell products and numerous BiAb trials. Data regarding outcomes after relapse following BiAbs are urgently needed to develop strategies for sequencing salvage therapies. We identified fifty-eight patients progressing after a BiAb trial at the Mount Sinai Hospital. Progression-free survival (PFS) to first- (PFS1) and second salvage therapy (PFS2), and overall survival (OS) were estimated using the Kaplan-Meier method. Patients had a median age of 67 years and 78% had high-risk cytogenetics. They had a median of 6 prior therapy lines, 89% were triple-class refractory and 44% were penta-drug refractory. After the BiAb trial, patients were followed for a median of 30.5 months and received a median of two additional salvage therapies (range: 1-9). The most common first salvage was T-cell redirection in nineteen patients (ten BiAb and nine CAR-T). Ten patients received T-cell redirection as second salvage. T-cell redirection therapy as first or second salvage was feasible and associated with a median PFS1 of 28.9 months and PFS2 of 30.9 months and an OS of 62% at 2 years. Sequential use of different T-cell redirection therapies is possible and can lead to deep and durable responses following relapse after BiAb therapy in RRMM.

CAR T‐Cell Therapy for Multiple Myeloma: A Clinical Practice‐Oriented Review

“…With the introduction of novel immunotherapies for MM, we also need a better understanding of optimal therapeutic sequencing by taking into account the effect of prior treatments on immune function and antigen expression patterns. 83,84 Patients who relapse after anti-BCMA CAR T-cell therapy can be potentially treated with multiple lines of salvage therapy, with a recent US cohort (n = 79) showing a median OS of 17.9 months in this setting. 85 Yet, the understanding of how prior T-cell redirection or BCMA-targeted treatment impacts the activity of anti-BCMA CAR T-cell therapy is still evolving.…”

“…85 Yet, the understanding of how prior T-cell redirection or BCMA-targeted treatment impacts the activity of anti-BCMA CAR T-cell therapy is still evolving. 83,84 In a phase I study, Cohen et al 86 demonstrated increased BCMA expression in patients with disease progression after CART-BCMA, suggesting that there is still potential to consider subsequent BCMA-targeting treatment. In most ide-cel trials, response rates to anti-BCMA CAR T-cells were found to be similar regardless of the level of BCMA expression.…”

T‐cell redirecting bispecific antibodies in multiple myeloma: Current landscape and future directions

“…Not only BsAbs targeting BCMA have shown great promise, but also BsAbs targeting other surface antigens on MM cells have substantial anti-MM activity (Table 1). Importantly sequential use of different T-cell immunotherapies is possible and can induce deep and durable remissions [46].…”

Single‐agent belantamab mafodotin in patients with relapsed/refractory multiple myeloma: Final analysis of the DREAMM‐2 trial

“…Along with these considerations, determining the optimal sequence within the current MM treatment landscape is critical, as the effectiveness of subsequent BCMA-directed therapies may be dependent on the baseline expression of BCMA or overall T-cell fitness. [22][23][24][25] Notably, recent data suggest that surface BCMA expression is not completely lost following belamaf treatment, 26 allowing possible subsequent treatment with other BCMA-targeting therapies, including other T-cell redirection therapies. 5,22,23,25 This final analysis of DREAMM-2 demonstrates a consistent and manageable safety profile over time for patients treated with belamaf.…”

“…[22][23][24][25] Notably, recent data suggest that surface BCMA expression is not completely lost following belamaf treatment, 26 allowing possible subsequent treatment with other BCMA-targeting therapies, including other T-cell redirection therapies. 5,22,23,25 This final analysis of DREAMM-2 demonstrates a consistent and manageable safety profile over time for patients treated with belamaf. The AE frequency was consistent with earlier reports Ocular events reported with belamaf treatment are a known class effect of MMAF-containing ADCs.…”