In a live virtual event, Jens Hillengass discussed the results of the MajesTEC-1 study and how teclistamab is used to treat patients with relapsed/refractory multiple myeloma. This is the second article in a 2-article series on this case.
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.
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.
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