Teclistamab Shows Strong Efficacy in Triple-Refractory Multiple Myeloma

Mansi R. Shah, MD

Assistant Professor of Medicine

Rutgers Robert Wood Johnson Medical School

New Brunswick, NJ

Targeted Oncology: What led to the approval of teclistamab-cqyv (Tecvayli) in patients with relapsed/refractory multiple myeloma?

MANSI SHAH, MD: It was based on the MajesTEC-1 study [NCT04557098]. It was a phase 1/2 multicenter trial. Importantly, it was investigating patients who had 3 lines of therapy or were triple-class exposed. It had typical standard inclusion criteria, with no prior BCMA [B-cell maturation antigen]-targeted therapy, and treatment was subcutaneous, which is important. It was given weekly after a step-up schedule. And the step-up is…day 1, 4, and 7; you have to wait about 48 hours in between each dose to monitor for cytokine release syndrome [CRS], as that is the biggest toxicity that can be limiting the next dose. They were looking at [the primary end point of] overall response rate [ORR] and the secondary end points were duration of response [DOR], depth of response, progression-free survival [PFS], overall survival [OS], and pharmacokinetics.¹

What were the baseline characteristics of the patients on the MajesTEC-1 trial?

Approximately 15% of the patients included in the trial were aged 75 or above, [which suggests] it’s pretty well tolerated. High-risk and hard-to-treat patients [were included]: extramedullary disease in about 17% and high-risk cytogenetics in about 26%. These were heavily pretreated patients. Most of them had greater than 4 prior lines of therapy, about 74%, and the median number of lines of therapy was 5. For this trial, about 30% were penta-refractory and about 78% were triple-class refractory. Most had an autologous stem cell transplant [81.8%].

What efficacy was observed with teclistamab?

The ORR was 63% and there were durable responses. Once they responded, they’re ongoing. Patients who had a complete response continued to respond. The median DOR was about 18 months, median PFS was 11.3 months, and median OS was around 18 months. Importantly, the ORR was consistent across high-risk cytogenetics and penta-refractory patients, and that’s the patient population who traditionally had very poor outcomes once they were penta-refractory. This is revolutionary in that situation. Response rates were lower in patients with extramedullary disease, high plasma cell burden, and high BCMA expression.

What are the most important safety and tolerability concerns with teclistamab?

[Teclistamab] works well, but what are the adverse events [AEs]? Most patients have cytopenias of some degree. The grade 3/4 cytopenias are less [frequent than grade 1/2], but neutropenia is definitely up there [64.2% grade 3/4 out of 70.9% any-grade AEs], which also leads to increased risk of infections. Sixty-three percent of patients required interruptions in ongoing dosing because of AEs. There were deaths, and these studies were doing were ongoing during the COVID-19 pandemic. There were 12 COVID-19–related deaths [out of 19 total AE-related deaths and other deaths were due to] a variety of AEs, including progressive multifocal leukoencephalopathy and pneumonia. CRS was high, [occurring in] 72%, but grade 3/4 CRS [occurred in only] about 1%. Neurotoxic events [of any grade occurred in 14.5%], which includes ICANS [immune effector cell–associated neurotoxicity syndrome]. It can be as subtle as a headache, which was included in the neurotoxicity AEs in this trial. It can be as severe as a coma, but we didn’t see that in this trial.

The CRS…was very predictable. With each step-up dose, there was a percentage of people who had CRS. With the first dose, it was 43%, 35% with the next dose, and 24% with the third dose. We can manage and anticipate some of the AEs. The median time to onset of CRS was about 2 days and duration was about 2 days. The study used tocilizumab [Actemra], an IL-6 inhibitor, to mitigate the AEs, but steroids were also used. One patient received low-dose vasopressors.

Is teclistamab only able to be given as an inpatient? Is it logistically challenging to give these medications in clinic?

The step-up dosing has been studied inpatient because of the CRS. Because the predictability of it, there are a lot of centers working how we can get these patients to outpatient and/or do a hybrid option.

It was [challenging] trying to work out the logistics and resource allocation…. But we are able to, if a patient needs it, get the drug. They are sharing the same resources as chimeric antigen receptor T-cell therapy and as autologous transplant, at some centers, but because these are a little bit more predictable, we can anticipate and shuffle things around to get the patients in. Some patients say, "No, you’re not admitting me for 7 to 9 days as we monitor for CRS." So they go in and out, or they start outpatient then go inpatient when we anticipate the highest risk of CRS.

In New Jersey, more and more community sites are getting this onboard. But I see a lot of patients only to start them [on teclistamab]. Then once the risk of CRS has diminished or is next to none, they go back to the community.

We’re working on getting mitigating strategies, ways to allow the patient to be at home or outpatient follow-up for these drugs. We’re already doing outpatient starting of these drugs in some selected patients, even from the beginning, if the patient is close, reliable, and has the support. In the trial they used tocilizumab, but steroids are cheaper, easy, and available.

_Reference:

_{1. 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}