The MajesTEC-3 trial is an ongoing randomised phase III trial for patients with multiple myeloma that is relapsed or progressing who have had 1-3 prior lines of therapy, so long as they had received a proteasome inhibitor, lenalidomide and steroids. The patients could have received prior anti-CD38 as long as the disease was not considered refractory to anti-CD38.

The main question of this trial was how does a total steroid-free immunotherapy approach with daratumumab, which now would be the starting block for any regimen in this population, plus teclistamab, a BCMA-directed T-cell engager, how does that compare with the standard of care, which would be daratumumab-based triplets, which is in this trial was either daratumumab, pomalidomide and dexamethasone or daratumumab, bortezomib and dexamethasone.

These patients were treated with the primary endpoint to be monitored was progression free survival with several secondary endpoints, including depth of response and overall survival, along with safety.

What was the study design?

The study, as I said, was a randomisation with stratification for number of prior lines of therapy, risk and, of course, the prior daratumumab exposure. The regimen on the control arm was administered as per standard of care, those are very well established, published and implemented regimens. On the teclistamab-daratumumab arm patients received daratumumab on day 1, they received step-up doses of teclistamab on day 2 and day 5, and then from day 8 onwards they received teclistamab at the full dose, 1.5mg/kg. Different from the prior approval of teclistamab in later lines of therapy. In this regimen the schedule matched the schedule of daratumumab, that being weekly for the first two cycles then every two weeks for cycles 3-6 and once every four weeks, or once per cycle, from cycle 7 onwards. The only difference was the dose of teclistamab, that was up to 3mg/kg, which is double the current dose, from the moment the patients went to the every-other-week dose.

What were the key results?

Of course the most key and most important finding was the primary endpoint, progression free survival. There was a huge improvement, a huge advantage, favouring the teclistamab-daratumumab arm. The patients had a reduction in the risk of progression and death with a hazard ratio of 0.17, which is the lowest hazard ratio ever reported on a myeloma trial, which in itself is very impressive.

If you look at the three-year mark, which was possible on this trial given the long follow-up of 34.5 months, the 36-month progression free survival was 83.4% on the Tec-Dara arm versus 29.7% on the DPd/DVd arm. This benefit in progression free survival was seen across all subgroups of interest including some subgroups that are difficult to treat, including patients 75 or older, patients with prior anti-CD38 exposure, patients with [??] high risk and patients with baseline plasmacytoma, as well as patients with high disease burden manifested by a high percentage of plasma cells in the bone marrow.

There was superiority for the Tec-Dara arm also in several other secondary endpoints for efficacy, including frequence and depth of response, with complete response or better being achieved in near 82% of patients on Tec-Dara and only 32.1% on the dara-based triplet combinations. Of course, that was also reflected in more patients achieving MRD negativity on the Tec-Dara arm than they did on the dara-based triplets.

One thing that was quite rare and fascinating to see is that even though this was the first interim analysis driven by a progression free survival event, we already saw an advantage, an improvement, in overall survival. The 36-month overall survival was 83.3% on the Tec-Dara arm versus 65% on the triplet arms with a hazard ratio of 0.46.

How was the safety profile?

There are several considerations to be made about safety. The early use of teclistamab in an era where we didn’t have such good immunoprophylaxis in a population that’s more advanced left concerns about the high rate of infections, particularly if you combine it with another agent like daratumumab. So it was very important to analyse the safety in this patient population.

The good news is that there were about 60% of patients with cytokine release syndrome, which is a signature toxicity from those therapies, but no patient had a grade 3 or higher cytokine release syndrome. There was only a little bit over 1% of ICANS and that was promptly reversed. So CRS and ICANS should not be limiting factors for administering of this transformational therapy.

The biggest concern has always been infection and we did, indeed, see a higher rate of infection in the Tec-Dara arm. But, importantly, the adverse events leading to treatment discontinuation were not more common on Tec-Dara, it was actually 4.6% versus 5.5%. The deaths due to adverse events were 7.1% on the Tec-Dara arm versus 5.9% on the triplet arm.

When you look at infections per se, the overall rate of infection was 96.5% in Tec-Dara and 84% on the control arm, and high grade infections 54% versus 43%. There were fatal infections, there were 30 in total in the experimental arm and there were four in the control arm. Now, it’s important to note that this trial was started back in 2021 before there was knowledge or implementation of infection mitigating strategies. So 12 of those deaths happened in the first six months and the vast majority prior to the introduction of mitigating strategies that included the administration of immunoglobulin, PJP prophylaxis, acyclovir, and more aggressive management of cytopenias, particularly [??]. After introduction of those measures, which happened after the vast majority of the patients had already been randomised and been treated for more than six months, there was one single death according to infections.

The risk of infection is really higher in the first six months and it was 35% on the experimental arm, the Tec-Dara, and 20.7% on the control arm. But, very interestingly, the risk was extremely close, very similar, in both arms from month 6 onward, which really tells us probably one of two things, or both things. That the biggest driver of infection is actually disease burden. We know myeloma itself is very immunosuppressive, once we lower the disease burden the risk of infection goes down. Second, it speaks for the efficacy of the mitigation strategies that we implemented, otherwise the risk would continue to be higher with Tec-Dara beyond the six months. Third, and importantly, is the dosing strategy employed in this trial with the administration of teclistamab mirroring the schedule of daratumumab, therefore less frequent dosing, that initially utilising teclistamab perhaps is contributing to also the greater safety of this combination.

What is the clinical significance of these results?

We believe these results are incredible and by outcomes provided the highest possible level of evidence to bring this therapy to the population in which it was studied, which are patients with 1-3 prior lines of therapy, len exposed, PI exposed, with the majority being len refractory. This is incredible because the options available now for this population are either less efficient or have complexity in administration, as in the case of autologous CAR T-cells, which are not so widely available as could be this T-cell redirecting therapy that is off the shelf and amenable to administration in the outpatients, in the community setting.

So this has the potential of bringing a transformational modality of therapy, which is a T-cell immunotherapy, to a setting where it was not possible before. Not to mention that this is the best performing therapy ever tested in a large study for patients with relapsed/refractory myeloma.