Teclistamab Elicits Efficacy in RRMM, Despite Prior Anti-BCMA Therapy

Ross Firestone MD, PhD

Among patients with relapsed/refractory multiple myeloma (RRMM), including those with prior anti-B-cell maturation antigen (BCMA) therapy exposure, teclistamab (Tecvayli) has proven to be an effective option, according to data presented at 2023 International Myeloma Society Annual Meeting.1

In a study presented by Ross Firestone MD, PhD, while responses to teclistamab were observed, they were reduced compared with patients naive to anti-BCMA therapies. However, positive outcomes were seen among those treated with commercial teclistamab.

Investigators observed that patients with enriched cytotoxic effector memory cells had a higher likelihood of response compared with those who had an abundance of T regulatory cells and other CD4-positive subsets, as these patients were less responsive. Firestone noted that this may be due to the competition for space on the CD3 binding arm for patients given teclistamab.

“We see that in this commercial teclistamab population, those with prior BCMA therapy exposure do have positive outcomes with teclistamab, albeit with a reduced response rate compared [with] patients that have naivety to anti-BCMA therapies,” said Firestone, fellow, hematology/oncology at Memorial Sloan Kettering Cancer Center, in a presentation of the data.

Teclistamab is a novel, off-the-shelf, CD3 x BCMA bispecific antibody which was approved in October 2022 for the treatment of patients with RRMM, based on the results of the MajesTEC-1 trial. The approval was granted for patients who have received at least 4 prior lines of therapy. Findings from the study showed that at a median follow-up was 14.1 months, the overall response rate (ORR) was 63.0% and the complete response rate was 39.4% among the 165 patients given teclistamab.²

However, when MajesTEC-1 was designed, patients with prior BCMA therapy exposure were excluded, leaving researchers still questioning the impact of teclistamab for this patient population.¹ As a result, an IRB-approved study sought to answer this question through evaluating BCMA-exposed patients with RRMM, while also using translational experiments to identify mechanisms of primary resistance that have potential to be identified before the start of treatment.

The study began by following a cohort of 52 commercially treated patients who received teclistamab at Memorial Sloan Kettering Cancer Center. Here, their efficacy and safety data were measured.

Baseline characteristics between the 52 patients enrolled and compared with patients included MajesTEC-1 showed that the commercial cohort was a bit older with a median age of 70 years (range, 39-88) vs 64 (range, 33-84) in MajesTEC-1. Patients had a worse performance status with a higher percentage of patients having an ECOG performance score greater than or equal to 1 in the commercial cohort vs in MajesTEC-1 (85% v 67%), and more patients were heavily pretreated with a median of 7 vs 5 prior lines of therapy. A greater proportion of patients in the commercial cohort were penta-drug refractory (67% v 30%), and most notably, patients in the commercial cohort had exposure to anti-BCMA therapies, with 52% of patients having exposure to any prior anti-BCMA therapy.

“When evaluating differences in progression-free survival in our population when stratifying by prior BCMA therapy exposure, we found that PFS was lower in the BCMA-exposed cohort in our population with an ORR to teclistamab of 50% in that group, and then we investigated further to see we identify the reasons for this difference,” said Firestone.

Experts then sought to determine if the decrease in efficacy correlated with loss of BCMA that resulted from prior BCMA therapy. Bone marrow biopsies were collected before the start of therapy from 31 of the 47 evaluable patients, and investigators measured BCMA-expression levels by immunohistochemistry.

The majority of patients had greater than or equal to 90% BCMA expression in the prior BCMA therapy group who were receiving teclistamab compared with those in the BCMA naive group (P =.17). When patients were stratified by whether they had a response to teclistamab by IMWG criteria, no differences were observed between patient populations (P =.56). Regardless of whether patients responded to their prior anti-BCMA therapies, the same BCMA expression was maintained.

Given that BCMA expression was present in nearly all patients, investigators questioned why there was so much heterogeneity in response. They looked at clinical datasets and absolute lymphocyte count measured prior to day 1 of cycle 1 of teclistamab among patients who had response and saw that some patients with grade 3/4 lymphopenia responded to teclistamab.

“Several of our patients with grade 3 or 4 lymphopenia were able to respond to therapy, implying that even a small inventory of circulating lymphocytes would be sufficient to allow for response,” added Firestone.

They stratified clinical outcomes by whether patients were diagnosed with cytokine release syndrome (CRS) during treatment or not. Data showed that patients with CRS had superior clinical outcomes than those who did not, implying that to get a strong response to therapy, immediate engagement by pre-existing immune cells may be needed.

Peripheral blood T-cell repertoire was profiled from pre-treatment peripheral blood mononuclear cell samples taken from 14 patients, including 9 responders and 5 non-responders of commercial teclistamab. The panel was T-cell focused, and used 37 colors, including lineage (CD4, CD8, CD25, CD127, CD45RA, CD45RO, CCR7, CD62L, CD28, CD95), exhaustion (PD-1, LAG3, TIM3, CTLA-4, TIGIT, OX-40, 4-1BB, ICOS, BTLA, CD57), activation (CD69, HLA-DR, CD25, CD27), and other markers.

Findings showed that among the teclistamab responders, there was enrichment for both CD8-positive effector memory T-cells (>6-fold increase, P =.03) and CD8-positive effector memory cells re-expressing CD45RA (>5-fold increase, P =.02). Non-responders to teclistamab were enriched for TIGIT-expressing regulatory T cells (Tregs) (3-fold increase, P=.03).

No differences between PD-1, CTLA-4, LAG-3 or TIM-3 expressions were observed in responders vs non-responders. There was also a high CD8-positive:CD4-positive ratio as predictive of response. Additionally, during step-up dosing, CRS was strongly associated with the efficacy of teclistamab.

Of the 31 response evaluable patients, the ORR for patients given commercial teclistamab with prior anti-BCMA therapy exposure was 58% (n = 11). This result was also similar for patients who were anti-BCMA therapy naïve.

“Additionally, there was slight expression of CD38 in this population, implying that targeting one of these two features may represent a T reg depleting therapy option, then we optimize the T cell population prior to treatment device specific antibody,” said Firestone.

There were no differences in BCMA expression between responding and non-responding patients in the study, as well as no difference between patients who were anti-BCMA exposed and anti-BCMA therapy naïve.

Overall, a pre-teclistamab T-cell population who have highly cytotoxic effector T-cells correlated with response to therapy. Conversely, nonresponse was associated with suppressive TIGIT-expressing Tregs. These data indicate a possible therapeutic role involving TIGIT blockade or CD25-positive cell depletion to enhance the efficacy of teclistamab, as well as other bispecific antibodies.

Firestone notes that further clinical and translational data from more patients will be presented at the meeting.

REFERENCE:

1. Ross Firestone. Bispecific T-cell engager response is driven by pre-treatment CD8+ effector memory cells and inhibited by TIGIT+ Tregs in relapsed/refractory multiple myeloma. Presented at: International Myeloma Society 20th Annual Meeting and Exposition; September 27-30, 2023; Athens, Greece. OA-03

2. Moreau P, Garfall AL, van de Donk NWCJ, et al. Teclistamab in relapsed or refractory multiple myeloma. N Engl J Med. 2022;387(6):495-505. doi:10.1056/NEJMoa2203478