Hello.
My name is Luciano Costa.
I'm a myeloma physician at University of Alabama at Birmingham.
Glad to be here at ASH 2025.
So at ASH 2025, we're going to have a late-breaking presentation on Tuesday.
My colleague, Dr. Maria-Victoria Mateo, is going to be presenting the first interim analysis of the MajesTEC-3 trial.
We're going to have a simultaneous presentation in a very prestigious journal.
This trial is very important. It is the first randomized phase three trial to test the value of bispecific T-cell engagers, in this case, teclistamab in combination with daratumumab.
In the MajesTEC-3 trial, we had nearly 600 patients who had disease exposed to proteasome inhibitors and lenalidomide, and the vast majority—over 80%—were refractory to lenalidomide.
They were then treated with a triplet containing daratumumab, either Dara-PD or Dara-bortezomib-dex, or daratumumab with teclistamab.
So it's the first time we see a triplet versus a doublet, where the doublet actually turns out winning.
Another interesting thing about this trial is the schedule of teclistamab. It was not weekly as currently approved for later lines—it actually completely mirrors clinical practice.
They dosed daratumumab weekly for the first two cycles, every other week for cycles 3 to 6, and once every four weeks from cycle seven onward.
After six months of therapy, patients have one appointment per month where they receive the teclistamab, daratumumab (two shots), and IVIG for supportive care, then return in four weeks.
This trial is very positive. It showed better progression-free survival and better overall survival.
On the first interim analysis, the reduction of risk of progression or death was 83%, the highest we have seen for any myeloma trial ever published. The reduction of risk of death was over 50%.
When we see these curves under presentation in the paper, it is very reassuring and gives a lot of hope. It seems there is a plateau on that curve.
Patients have very few progression events beyond six months, and that plateau is above 80%, giving the perception that some of those patients may have reached a functional cure and might not need additional myeloma therapy for the remainder of their lifetime.
Of course, that is a big claim to make. We need longer follow-up, and we will ultimately need ways to de-intensify therapy for those patients.
Another great lesson from this trial is that we initially had the impression that teclistamab with daratumumab would be excessively toxic. Early experience from four or five years ago, in more advanced disease during the pandemic, showed many infections, including fatal infections.
In this trial, there were some deaths due to infection—13 in a population of almost 100 patients, mostly in the first six months, before the introduction of mitigating measures such as IVIG, Bactrim prophylaxis, and mandatory VZV prophylaxis.
Since the introduction of these measures in 2023, there has been only one single death related to infection.
Importantly, after six months, we are not seeing those infections. The rate of infection is the same on both arms. This therapy does not appear more dangerous than the control arm for patients six months and beyond.
This highlights the importance of infection-mitigating strategies.
We expect that eventually this regimen will gain regulatory approval, bringing patients an option of off-the-shelf, steroid-free, outpatient T-cell redirecting therapy that is safe when given with infection-mitigating strategies, namely acyclovir, Bactrim prophylaxis, and monthly IVIG.
HealthTree • December 16, 2025