MajesTEC-1 Results Show Efficacy for Teclistamab in Multiple Myeloma

CASE SUMMARY

A 63-year-old man, who was diagnosed 8 years ago with IgG-κ multiple myeloma, presented with penta-refractory disease progression after 4 prior lines of therapy, including autologous stem cell transplant, 2 proteasome inhibitors (PIs), 2 immunomodulatory drugs (IMiDs), and 1 anti-CD38 antibody. His personal medical history included hypertension controlled with lisinopril and he had ECOG performance score of 1. The patient asked about CAR (chimeric antigen receptor) T-cell therapy, but after counseling, opted to pursue an alternative therapeutic due to waiting lists at accessible institutions.

Targeted OncologyTM: Please discuss the format of the MajesTEC-1 (NCT04557098) study.

HILLENGASS: The MajesTEC-1 study design was the first-in-human, phase 1/2, open-label, multicohort, multicenter, dose-escalation study evaluating teclistamab (Tecvayli) in patients with relapsed/refractory multiple myeloma.1 Patients had to have 3 or more prior lines of therapy, and they were triple-class exposed. [Moreover, they had to have] at least been exposed to an IMiD, a PI, and a CD38-antibody. The treatment was [then given] weekly with teclistamab given subcutaneously at 1.5 mg/kg, and then they had a follow-up after the last patient was enrolled at 2 years.

Jens Hillengass, MD, PhD

Chief of Myeloma

Professor of Oncology

Roswell Park Comprehensive Cancer Center

Buffalo, NY

The primary end point was overall response rate [ORR], which is the lowest level that we can afford in clinical trials. Key secondary end points included duration of response [DOR], very good partial response [VGPR] or better, complete response [CR] or better, stringent CR, time to next treatment, minimal residual disease status, and progression-free survival [PFS]. Overall safety, pharmacokinetics, immunogenicity, and patient-reported outcomes [were also looked at].

[All] of the 165 patients [enrolled in the trial] were triple-class exposed because it was inclusion criterion. Investigators enrolled [patients with] latest lines of therapy or the most pretreated patients in these trials, and so 70% of patients were penta-drug exposed. There were also a significant number of elderly patients, which I think is important and interesting, because not all our patients are in their 60s. Most of them are not.

As in all myelomas, a bit more patients were male. There was a number of African-American patients; oftentimes a problem is that these trials are very Caucasian heavy in their enrollment. Then, what was also observed was extramedullary plasma cytomas, which are a bad prognostic marker, and that was present in 17% of patients, so also significant. Triple-class refractory stage was seen in 77% of patients, which are the patients that we talk about here.

What were the efficacy results of MajesTEC-1?

The ORR was 63% with a significant number with VGPR or better at 39.4% (n = 65).1 At the data cut-off, 64% had also maintained their response. The median DOR was 18.4 months, which is impressive in these patients. Then, the median PFS was 11.3 months—almost a year of PFS in that line of therapy. The median OS was 18 months, but it is not mature.

ORR was seen in all the clinically relevant subgroups, including high-risk and penta-drug refractory subgroups. Some patients were in a long remission. We were a little bit disappointed when we saw this great ORR, but then early relapses.

The CAR T-cell therapies are better, at least when it comes to the response rate, but…unfortunately, they have to be admitted [in order to complete treatment] at the moment. That's FDA required.2 So, for the step-up dosing, they're inpatient [while it’s administered].

What were the relevant safety data for patients with relapsed/refractory multiple myeloma?

Every patient had an adverse event [AE], and 95%—that's impressive on the negative side—had a grade 3 or 4 AE.1 The discontinuation rate because of AEs was only 1.2%: adenoviral pneumonia and progressive multifocal leukoencephalopathy [PML], and then there was a dose reduction in 1 patient at cycle 21, which is fairly late. Overall, 63% of patients skipped doses, and infections were seen in 76% [of patients].

Evidence of hypogammaglobulinemia was 74.5%. Deaths due to AEs occurred in 19 patients; 12 were COVID-related deaths. Teclistamab-related AE deaths were seen in 5 [patients]. So, it's always depending on if it's related to teclistamab or to something else, and the teclistamab-related AE deaths were with COVID, pneumonia, hepatic failure, and PML.

How was cytotoxicity handled with this teclistamab?

A lot of patients had neutropenia [70.9%, grade 3 and 64.2%, grade 4], anemia [52.1%, grade 3 and 37%, grade 4], and thrombocytopenia [40.0%, grade 3 and 21.2%, grade 4]. Basically every patient had some kind of cytopenia. Then, the new AE on the block is the cytokine-release syndrome [CRS].

There are guidelines regarding CRS, which at the moment is mostly [to keep them] inpatient. If it happens, it's important, especially if a patient develops it in a later line of treatment. It's rare later on, but it still can occur. The CRS [rate in this study] was 72%, but not too many grade 3 [0.6%] and no grade 4 events, but there was also neurological toxicity.

Those are the events that we knew already from the CAR T cells, the [immune effector cell-associated neurotoxicity syndrome], and the immune therapy-related neurological syndrome [seen in 5 patients]. The most frequent neurotoxicity’s were headaches, followed by motor dysfunction and sensory neuropathy, while 13% [of patients] had encephalopathy, which we know from CAR-T cell treatment as well.

That's the reason why a step-up dosing was recommended for the approved drug now, as well. It's even recommended to have these patients go 48 hours as an inpatient. Step-up dosing is on day 4, so the first full-treatment dose is on day 7. Thereafter, it will be weekly, and the recommendation is to keep these patients’ inpatient for 48 hours after every dose.

^References:

^{1. Moreau P, Garfall AL, van de Donk NWCJ, et al. Teclistamab in Relapsed or Refractory Multiple Myeloma. N Engl J Med. 2022 Aug 11;387(6):495-505. doi: 10.1056/NEJMoa2203478}

^{2. FDA approves teclistamab-cqyv for relapsed or refractory multiple myeloma. FDA. October 25, 2022. Accessed May 9, 2023. https://bit.ly/41z5qFv}