Teclistamab Triplet Elicits Clinical Activity in R/R Multiple Myeloma

Emma Searle, MBChB, PhD, MA, MRCP, FRCPath

The combination of teclistamab (Tecvayli), daratumumab (Darzalex), and lenalidomide (Revlimid), led to encouraging clinical activity in patients with relapsed/refractory multiple myeloma (RRMM), according to findings from the phase 1b MajesTEC-2 trial (NCT04722146).

At a median follow-up of 8.4 months (range, 1.1-12.9), the overall response rate (ORR) was 93.5%. Very good partial responses or better were achieved by 90.3% of patients. Additionally, 54.8% of patients achieved a complete response or better. Responses deepened over time, and according to findings, the median duration of response had not been reached.

The most common grade 3/4 hematologic adverse events (AE) seen with the combination therapy included neutropenia (78.1%), thrombocytopenia (15.6%), and febrile neutropenia (12.5%). For non-hematologic AEs, the majority were low-grade, and any-grade cytokine release syndrome occurred most frequently among 81.3% (n = 26) of patients and lasted for 2 days, on average.

Other safety findings showed that most infections observed in patients were low-grade and the most common grade 3/4 infections were pneumonia (15.6%), COVID-19 (12.5%), and sepsis (9.4%). Two patients had AEs which resulted in death, including 1 related to COVID-19 and 1 from multiorgan failure due to sepsis.

According to Emma Searle, MBChB, PhD, MA, MRCP, FRCPath, teclistamab will continue to be evaluated in the triplet regimen with daratumumab and lenalidomide (Lenvima) vs daratumumab (Darzalex), lenalidomide, and dexamethasone in patients with newly-diagnosed multiple myeloma who are transplant-ineligible or in the randomized, open-label phase 3 MajesTEC-7 trial (NCT05552222).

“That is an important study to help us understand how these potent immunotherapy combinations fare against the standard of care that we're all used to using in a head-to-head comparison,” Searle, consultant hematologist at the Christie Hospital NHS Foundation Trust, and honorary senior lecturer at the University of Manchester, told Targeted OncologyTM, in an interview.

In the interview, Searle further discussed results from cohort E of the MajesTEC-2 study of teclistamab in RRMM.

Can you discuss teclistamab and where it has been researched so far?

Teclistamab is the first off-the-shelf CD3 BCMA bispecific antibody. It was previously studied as monotherapy in the MajesTEC-1 trial [NCT04557098], and alongside daratumumab in the TRiMM-2 study [NCT04108195]. This data is from 1 cohort in MajesTEC-2 [NCT04722146], in which teclistamab was used alongside daratumumab and lenalidomide and some more agents to give us a feel for how these how teclistamab behaves in combination in terms of safety and efficacy, and how it might be useful as an early line of therapy.

Can you talk about the methods and design in this study?

In the MajesTEC-1 study, patients were heavily pretreated, whereas in this study, it's patients who've received between 1 and 3 prior lines of therapy. This is a non-randomized phase 1b trial. There were several different cohorts across the trial overall. But the cohort that I've presented on, cohort E, which was teclistamab started at the beginning of cycle 1. We tested a couple of different dosing regimens. But after step-up dosing, teclistamab was given weekly. Daratumumab was also started in cycle 1, and then we added in lenalidomide at the start of cycle 2. All patients in the cohort received the same treatment, other than the differences in teclistamab dosing. We treated 32 patients in total.

Please discuss the findings from the MajesTEC-2 trial.

What we've learned about teclistamab, when you [look at] cohort E from MajesTEC-2 trial is that when you use teclistamab in combination with daratumumab and lenalidomide, you certainly see higher responses than we saw when we used this in monotherapy. In the monotherapy trial, the ORR was 63%, and the ORR in this combination across both dosing groups was 94%, so it was very high. We saw deep remissions, so 55% of patients had achieved CR or better at the points that we analyzed the data ahead of ASH. If I look at the patients at the lower teclistamab dosing where the data is slightly more mature, we had a median follow-up of 11 months as opposed to 8.4 [months] across the whole study. In general, the response rate was 100%, so these are powerful anti-myeloma combinations.

CRS is something we always worry about with the bispecific antibodies. We did see that CRS was common, but it was all low grade. It was all grade 1 or 2; we didn't see any cases of grade 3 or 4 CRS, and we didn't see any ICANS, which is important as we plan on using these therapies. Neutropenia was a frequent event, and as the study went on G-CSF use was encouraged to help manage that [AE]. Fortunately, febrile neutropenia was a much less common event. In the main, [neutropenia is] something we're picking up on the blood tests, but the patients were well.

The other adverse event we are conscious of, and we need to be vigilant for as we move forward in combination studies is infection. Ninety percent of patients experienced an infection at some point during their treatment. The majority of those infections were mild, but a third of patients had more serious infections, and those infections were predominantly COVID-19 or respiratory tract infections and pneumonia. Sadly, we did lose 2 patients after the first 2 were treated in this cohort to infection. One death was from COVID-19, and the other from multiorgan failure from sepsis. That's an important learning point going forward.

In terms of where we are going next with teclistamab, we've got the up-and-coming MajesTEC-7 study plans now in which teclistamab, daratumumab, and lenalidomide will be compared with dexamethasone. That is an important study to help us understand how these potent immunotherapy combinations fare against the standard of care that we're all used to using in a head-to-head comparison.

What unmet needs still exist in this space?

I still think we've got a lot to learn about immunotherapy. We don't know how long we should be treating for. We don't know [if] we need to maintain the same dosing intensity. In the MajesTEC-2 trial, increasingly, we moved to longer dosing intervals. In this cohort, we moved to weekly dosing, but, in other cohorts in this study, there were longer dosing intervals. We do need to understand more about how to keep patients safe on these treatments. And we need to understand more about what line of therapy to use them at. Intuitively, we always think that we should use our most efficacious agents as early as possible. But we don't have the data yet to tell us where and when to use them. [There is] lots of research to be done.

REFERENCE:

Searle E, Quach H, Wong SW, et al. Teclistamab in combination with subcutaneous daratumumab and lenalidomide in patients with multiple myeloma: results from one cohort of MajesTEC-2, a phase 1b, multicohort study. Presented at: 64th American Society of Hematology Annual Meeting and Exposition; December 10-13, 2022; New Orleans, Louisiana. Abstract 160.