Expedited FDA Approval of Teclistamab for Relapsed/Refractory Multiple Myeloma

Ajai Chari, MD, discusses the FDA approval of teclistamab for relapsed/refractory multiple myeloma and data from the MajesTEC-1 trial that led to this approval.

On October 25, 2022, the US Food and Drug Administration (FDA) granted expedited approval to teclistamab-cqyv for adult patients with relapsed/refractory (R/R) multiple myeloma (MM) who have received ≥4 prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody.

Transcript:

Hello, my name is Ajai Chari. I'm professor of medicine and director of clinical research at the Icahn School of Medicine at Mount Sinai, New York.

OLN: What is teclistamab?

Teclistamab is an exciting new drug approval for myeloma patients. It's basically a bispecific. It's interesting—every monoclonal antibody in humans actually owes its legacy to myeloma, because back in the '80s there was an antibody created by fusing a myeloma cell to a spleen cell. And what's unique about this particular antibody is that historically, antibodies just bind 1 target. Here you're binding 2 targets. One is the T-cell with a CD3, and the other is the BCMA or B-cell maturation antigen, which is bound by the other part of the antibody. What this does is traffics a patient's own T cells to the myeloma, and then when the T cells recognize the myeloma as being foreign, they release perforin enzymes which pokes holes in the membranes of the myeloma cell and results in apoptosis. So, basically you have targeted cell killing of the myeloma cell.

What data led to the recent FDA approval?

The approval that we have from the FDA is based on an accelerated approval strategy, which is a single-arm study. They used 110 patients. There's actually a larger number of patients that were reported out in the New England Journal. But historically, to get a drug approved in patients with an unmet need, which is defined as patients who've exhausted all available therapies, the benchmark was about 20% to 30% response rate, and the [progression-free survival] PFS used to be about 3 to 4 months. And here teclistamab as a single agent had a response rate of over 60%, and the PFS was over 11 months, and the median duration of response based on the New England paper that came out this August was actually over 18 months.

To get these kinds of numbers in patients who could have gone to hospice is really a gamechanger, we can't emphasize enough what a breakthrough this is. Particularly given, while we have CAR-Ts that have also been approved but what's unique about teclistamab, it's off the shelf. It's ready to go. When a patient needs it, it's available. And that's really a very big distinction from CAR-T, which has quite a lengthy process to get through the whole thing.

What is the current treatment landscape for patients with relapsed/refractory MM? How does teclistamab fit into that treatment paradigm?

The current landscape of myeloma has dramatically changed since when I was in training. Historically we had conventional chemotherapeutics and steroids, but in the last few decades we've had the immunomodulatory agents, the proteasome inhibitors, the immunotherapeutics, including naked antibodies, if you will, and the XPO1 inhibitor known as selinexor.

In this particular study, patients had to have at least 3 prior therapies, including 3 of the fundamental backbones. And the reason that is important to know about is that we know from natural history and real-world data that patients who are triple-class refractory, and some are even penta-drug refractory—which means all the drugs really, the big 5 drugs that are available, which is lenalidomide, pomalidomide, bortezomib, carfilzomib, and either daratumumab or isatuximab. But historically, that patient population has a really dismal prognosis of 6 to 9 months overall survival. To be getting these kinds of responses in that unmet need is really dramatic.

What is the safety profile of teclistamab?

The main new safety profile that I think folks in the community need to be aware of, in terms of recognizing and managing, is cytokine release syndrome (CRS). This is a common side effect that we see in T-cell redirection therapy, when the T cells are activated and kill the myeloma cell, they can produce cytokines. And cytokine release syndrome can manifest with fever, sometimes low blood pressure, oxygen, and rarely more serious. But in this particular agent, most of the CRS, which is quite common, over 70%, tended to be low-grade. We don't see a lot of grade 3 and 4.

There is a [risk evaluation and mitigation strategy] REMS program for this agent that requires that the drug, first of all, per the label, is given in what we call a step-up dosing fashion, so it's not the full dose all at once, but gradually increased. And the labels suggest that patients should be observed in the hospital for 48 hours after each dose. So that's one side effect to be aware of. And then the other things to be aware of are neutropenia, which particularly cytopenias we see in the first few cycles.

The other side effect is infections. We know that patients targeting BCMA with many different types of therapy can get hypogamma, and so that is seen in up to 70% of patients. But probably in addition, there may be some immune modulation. And so it's important to prophylax patients for COVID with boosters, and then also at the time of COVID, they get the therapeutics that are available, whether it's oral or Perenterol, based on the strains. And then also [intravenous immunoglobukin] IV-Ig is probably beneficial to prevent the recurrent infections.

Those are the 3 main things: CRS, infections, and COVID-related issues. There are rare neurologic toxicities known as [immune effector cell-associated neurotoxicity syndrome] ICANS, which can be observed by decreases in alertness. There's an [immune effector cell] ICE scale that can be used to characterize a patient's alertness. But typically that's happening in that CRS time period, in the initial few doses. But these are all quite manageable. Overall, I think the PFS and the duration of response were really outstanding.

Will this approval have an immediate impact in real world practice?

Absolutely. There is an ever-increasing number of patients who've exhausted these therapies that we talked about, and there are some agents, but some of those agents are hampered by toxicity or limited efficacy, and then some are constrained by access, like the CAR-Ts. So this is a highly efficacious agent, but it's off the shelf. I think it's going to be in great demand. And I could tell you at our institution, we already have quite a list of patients that we're excited to get going on this therapy, and it'll literally be life-extending for them. It’s very exciting.

What are the next steps for investigating teclistamab in this or other populations?

Accelerated approval needs to have confirmatory studies. So that typically is done in a setting of randomized study in earlier lines of therapy. Teclistamab is being compared to standard-of-care agents. And the other thing in myeloma is also these drugs typically move up earlier, in earlier lines of therapy, and also in combination. So those are the 3 different things. Phase 3 trials, earlier lines, and combination studies are all ongoing, so we eagerly await those data sets. It's a very exciting time.

Sources:

1.     FDA approves teclistamab-cqyv for relapsed or refractory multiple myeloma. Press Release. The US Food and Drug Administration. Published online October 25, 2022. Accessed January 30, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-teclistamab-cqyv-relapsed-or-refractory-multiple-myeloma

2.     Moreau P, Garfall AL, van de Donk NWCJ, et al. Teclistamab in Relapsed or Refractory Multiple Myeloma. New Eng J Med. Published online June 5, 2022. doi:10.1056/nejmoa2203478