Reengaging life post-BCMA for myeloma

In this issue of Blood, Touzeau et al¹ found that patients with myeloma previously treated with B-cell maturation antigen (BCMA)-targeted therapy (TT) responded well to the anti-BCMA T-cell engager (TCE) teclistamab. These data are crucial for evaluating treatment options in the evolving landscape post-BCMA-targeted therapies.

BCMA-TTs have been a breakthrough in the treatment of relapsed refractory multiple myeloma. Both chimeric antigen receptor T cells (CAR-T) and bispecific antibody (BsAb) TCE) rely on T-cell function, with T-cell fitness being predictive of clinical response to these agents.² In contrast, the antibody drug conjugate (ADC) belantmab mafodotin (belamaf) relies on antibody-dependent cellular cytotoxicity via binding of Fc receptors to natural killer cells and monocytes, direct induction of apoptosis via internalization and release of the monomethyl auristatin-F cytotoxic payload, and inhibition of prosurvival signals through BCMA receptor blockade.³ Although cases of downregulation or loss of BCMA have been described post-BCMA-TTs, in most cases, BCMA expression is maintained, indicating that retargeting BCMA with a different modality of action is possible. However, the optimal sequencing of these agents remains unknown. Thus, the optimal management of patients who relapse after anti-BCMA therapy has emerged as an unmet need.

In this issue, Touzeau and colleagues reported the outcome of cohort C of the phase 1/2 MajesTEC-1 study, which enrolled 40 patients who had been exposed to anti-BCMA (ADC [n = 29], CAR-T [n = 15], or both [n = 4]). Here, the overall response rate to teclistamab was 52.5% (complete response or better 30%), which was not much lower compared with what was seen in the BCMA-naive cohort of the MajesTEC-1 study. However, the median progression-free survival (PFS) of 4.5 months fell short of the 11.3 months found for patients who were BCMA-naive. Notably, the efficacy of teclistamab was similar between the cohort with prior BCMA-targeted ADC and CAR-T therapy. Those who responded did well, with a median response duration of 14.8 months (16.7 months for those who achieved at least a complete remission [CR]), and the overall survival of the whole cohort was 15 months. Although the outcome was shorter than those for patients who were BCMA-naive, it is remarkable for a group of patients who were quadruple-class refractory. This validates the real-world experience that retargeting BCMA is feasible.⁴ It also raises the question of how to identify those likely to respond to BCMA retargeting and which biomarkers can aid in the optimal sequencing of BCMA-directed agents in relapsed/refractory multiple myeloma.

In patients with prior anti-BCMA exposure, predictors of response to the BCMA CAR-T, cilta-cel, were (a) shorter duration of prior exposure to BCMA-TT and (b) longer interval from last anti-BCMA treatment.⁵ Conversely, in those patients with prior BCMA-ADC exposure receiving the BCMA TCE teclistamab, Touzeau and colleagues showed that responders had a shorter interval between last anti-BCMA-TT and teclistamab (median 108 days, range 39-988) compared with nonresponders (median 265 days, range 22-1144). The same was not seen in the cohort with prior anti-BCMA CAR-Ts, although the number of patients in this cohort was limited. Altogether, these observations raise the question of whether belamaf, because of the impact on immune effector cells,⁶ can improve response to subsequent BsAb TCE but not necessarily CAR-T therapy.

When sequencing BCMA-TTs (see table), it is intuitive to expect that prior CAR-T therapy would negatively impact the subsequent response to BCMA-BsAb due to T-cell exhaustion. However, this report did not observe such an effect, although the patient number was limited. The rate and depth of response to teclistamab were similarly robust in both cohorts, as was the duration of response. In a pooled analysis from MagnetisMM studies,⁷ prior CAR-T therapy did not negatively impact the subsequent response to the BCMA BsAb elranatamab. Likewise, prior BCMA BsAb exposure did not appear to result in a worse outcome to BCMA CAR-T therapy compared with prior BCMA-ADC. Response to ide-cel and cilta-cel was 86% and 57%, respectively, in 2 small reported-cohorts.^5,8 Experience with BCMA-ADC in patients with prior BCMA BsAb or CAR-T therapy is limited. However, the scarce available data suggest that BCMA-ADC has poor activity in these patients, at least as a monotherapy.⁹ Much remains unknown; perhaps immune profiling is necessary in the future to provide the predictive biomarkers.

Managing patients post-BCMA-TT will be more common going forward as these agents are moved to earlier-line therapy. In addition to retargeting BCMA with a different therapy, other effective salvage options may include non-BCMA-targeted BsAbs and CAR-Ts (eg, G protein-coupled receptor class C group 5 member D and Fc receptor-homolog 5). In early line relapse, where all treatments have not been exhausted, other non-T-cell redirection therapies may also prove effective after BCMA-TT relapse. Potential options include cereblon E3 ligase modulatory drugs (CELMoDs), exportin-1 inhibitors, and standard combinations of second-generation immunomodulatory drugs (IMIDs) and proteasome inhibitors not yet received. For patients who were heavily pretreated, sequential use of T-cell redirection therapies appears most promising, although evidence is limited to real-world reports and small prospective studies. Thus, the challenge ahead is not only to identify biomarkers of response to retargeting BCMA, but also to explore how best to reengage responses to different T-cell redirection therapies. We know that BsAb TCEs rely on a robust CD8⁺ cytotoxic T-cell response; however, continuous antigen stimulation leads to T-cell exhaustion.¹⁰ Therefore, for BsAb TCEs, exploring a finite treatment duration, as opposed to treatment until disease progression, should be prospectively studied to allow for the reversal of T-cell exhaustion and improve response to subsequent T-cell redirection therapies. Alternatively, introducing treatment-free intervals in an “on-off” staccato approach may also curb T-cell exhaustion, as has been suggested by preclinical studies.¹⁰ Studies exploring rational combinations or sequential treatments with agents that potentially enhance T-cell function, such as IMIDs, CELMoDs, or checkpoint inhibitors, are also underway.

In summary, the data reported by Touzeau and colleagues herald exciting times ahead as ongoing prospective studies and expanding real-world data provide deeper insight into optimal sequencing strategies for BCMA-TTs. Advanced tools for assessing immune fitness and antigen expression may also help predict which patients will benefit from retargeting BCMA.

Conflict-of-interest disclosure: H.Q. received research support from AbbVie, GlaxoSmithKline (GSK), Bristol Myers Squibb (BMS), Sanofi, Amgen, Karyopharm, and Antengene and is on advisory boards for AbbVie, Roche, GSK, BMS, Sanofi, Johnson & Johnson, and Regeneron.