Bispecific Combination Shows Durable Responses in Multiple Myeloma

Yael C. Cohen, MD

Bispecific agents are one of the latest successful classes of therapeutics to make an impact in hematologic malignancies. The approval of teclistamab (Tecvayli) for patients with relapsed/refractory multiple myeloma has paved the way for the investigation of other drugs in disease settings with urgent need for new agents, especially off-the-shelf therapies that can be given more quickly than chimeric antigen receptor (CAR) T-cell therapy.

The RedirecTT-1 trial (NCT04586426) is the first to combine 2 bispecific T-cell engagers, teclistamab and talquetamab. Teclistamab targets B-cell maturation antigen (BCMA) on multiple myeloma cells, whereas talquetamab targets GPRC5D, and both target CD3 on T cells to induce an immune response. The first results from this trial were presented at the 2023 American Society of Clinical Oncology Annual Meeting (ASCO 2023).¹

The phase 1b dose escalation trial enrolled 93 patients, 34 of whom received the recommended phase 2 regimen (RP2R) dose of the combination. Additionally, investigators observed a high overall response rate (ORR) with durable responses and no added toxicity from the combination. The patient population included 35 patients (37.6%) with extramedullary or soft tissue plasmacytomas, 11 of whom received the RP2R with an ORR of 85.7%.

In an interview with Targeted OncologyTM, Yael C. Cohen, MD, senior physician in the Department of Hematology at Tel Aviv Sourasky Medical Center in Israel, discussed the results from RedirecTT-1 she presented at ASCO 2023.

Targeted Oncology: Could you describe the trial that you presented at ASCO 2023?

COHEN: I presented data from the RedirecTT-1 trial. It's a phase 1b trial of the combination of teclistamab and talquetamab in patients with relapsed/refractory multiple myeloma. This is the first trial to be reported ever that combines 2 bispecifics in any human malignancy, so it's really exciting.

Could you discuss the methods and design of this trial?

Being a phase 1b trial, we employed the extensive dose escalation measure to get to the RP2R. This ended up being teclistamab at 3.0 mg/kg and talquetamab at 0.8 mg/kg [every 2 weeks]. We had step-up dosing all the way [to the RP2R dose]. The patients included in the trial were patients who were relapsed, refractory, or intolerant to established treatments in myeloma, and they had to be refractory to their last treatment line.

There were 93 patients who were included overall and of them 34 [received the] RP2R, and the median age was 65. They had a median of 4 prior lines of therapy. About a third of the patients had soft tissue plasmacytoma. This is a condition which is typically quite hard to treat. Over 20% had prior BCMA exposure, 75% were triple class refractory, and 90% were refractory to their last line of treatment. All in all, this is a quite [challenging] patient population.

What were the findings from the first results of the RedirecTT-1 trial?

As far as safety [goes], there were no surprises; the safety was manageable and was comparable with that of the monotherapies. [In terms of] hematologic toxicities, there was a rate of 12% febrile neutropenia. As far as non-hematologic [toxicities], there were few discontinuations. We had a high rate of infections, as can be expected and is typical for bispecifics, but less than 40% of the patients at RP2R had a grade 3 or 4 infection. There were 6 deaths on the study due to infections. The cytokine release syndrome [CRS] rate was also comparable with what we are accustomed to. Most [events] were grade 1 or 2 CRS, and 26% of the patients required tocilizumab [Actemra]. There were 5 cases of ICANS [immune effector cell–associated neurotoxicity syndrome]; however, only 1 was a transient grade 3 and the rest were grade 1 events. All in all, safety was manageable with a low rate of discontinuation.

Switching to efficacy, we're in 14 months of follow up for the entire cohort and 8 months for the RP2R efficacy. The ORR was very high in this very tough patient population. We saw an 86% ORR in the entire cohort and 96% in the RP2R cohort, and these responses were very durable at the data cut-off. We know that over 60% of the patients, 57 patients, are still on treatment. The responses were rapid—within 2 months—and they were durable. At RP2R, the duration of response (DOR) was not reached.

When we dive into those patients with soft tissue plasmacytoma—and it's important to emphasize that in this study, these were truly soft tissue, not arising from bone, not skeletal—we know that this kind of myeloma is difficult to treat and off-the-shelf treatments produce a rate of response ranging between 5% and 40%. CAR T cells have higher responses; however, they have limited durability. Here we have 85% ORR in the RP2R patients with soft tissue plasmacytoma with durable responses [and] DOR not reached with the RP2R, so this is quite a big breakthrough for these patients with soft tissue plasmacytoma.

In conclusion, [this was] the first time 2 bispecifics were combined, [with] very high efficacy, 96% ORR at RP2R and 85% [ORR in] patients with soft tissue plasmacytoma, a tough group. There was no excess toxicity beyond what we are familiar with for the monotherapy. Putting all this together, we are hoping for further studies with this combination, and a cohort of soft tissue plasmacytoma is going to open for enrollment shortly.

What would you say are the key takeaways, especially for community oncologists?

The key takeaways are that this is another big leap forward in the treatment of relapsed/refractory myeloma with efficacy that looks beyond what we were used to be seeing before. This is an encouraging message for our patients. We're going to be able to extend more lives and this is quite a convenient treatment because at 7 cycles, patients switch to once monthly subcutaneous injections. This is also very manageable from a logistical point of view.

_Reference:

_{1. Cohen YC, Morillo D, Gatt ME, et al. First results from the RedirecTT-1 study with teclistamab (tec) + talquetamab (tal) simultaneously targeting BCMA and GPRC5D in patients (pts) with relapsed/refractory multiple myeloma (RRMM). J Clin Oncol. 2023;41(16_suppl):8002. doi:10.1200/JCO.2023.41.16_suppl.8002}