In the MajesTEC-1 study, we enrolled patients with multiple myeloma who were heavily pretreated. So, all the patients were exposed to CD38 antibodies, to immunomodulatory drugs and proteasome inhibitors. In fact, three-quarters of the patients were refractory to all these three different drug classes, so-called triple class refractory disease. In the MajesTEC-1 study, these heavily pretreated multiple myeloma patients were treated with teclistamab monotherapy. In fact, 165 patients were treated with teclistamab at the recommended phase II dose of 1.5mg/kg with two step-up doses to mitigate cytokine release syndrome. 

What was the study design?

So patients with triple class exposed multiple myeloma were treated with teclistamab at the recommended phase II dose after two step-up doses. Teclistamab was given once weekly but patients had the opportunity to get to a less frequent administration schedule of teclistamab. If they had achieved a complete remission for more than six months in phase II, they could switch to every two week dosing, or the patients in phase I could switch to every two week dosing if they had achieved a partial response after 4 months. And if there was continued clinical benefit, patients could also move to a once monthly schedule. So most of the patients that are still in the study at this moment are having a less intensive teclistamab administration schedule of either every two weeks or every month. 

What were the results of the study?

So with a follow-up now of two years, we see an overall response rate of 63%, which is similar to the last data cutoff. But what we see with extended follow-up is that the frequency of complete remission is increasing to 45%. This is a very high percentage of CR because this patient population was mostly triple class refractory and typically when you treat this patient population with standard of care outside of a clinical trial we see a complete remission rate of lower than 5%. So 45% is really outstanding. We also see, with a median follow up now of two years, that the median response duration has increased to 22 months for the whole patient population. When you achieve complete remission, the median response duration was even 27 months. 

Median PFS remains stable at 11 months and was 27 months for patients who achieved complete remission. We also have now more mature data on overall survival and for the whole patient population median overall survival was almost two years at 22 months. For patients with CR median, overall survival was not yet reached. This median overall survival of almost two years is also much better than you would see in this patient population when you treat them with a standard of care regimen, then you see, for example, in LocoMMotion, a median overall survival of only 12 months. So we see a doubling in the overall survival.

Also important is to discuss safety with this longer follow-up and we see that there is no increase in cytokine release syndrome, no significant alteration in other side effects. However, there was a slight increase in infections over time but the increase in infections is flattening. We think that this flattening in the frequency of serious infections might be related to the fact that we are now giving teclistamab every two weeks or every month and maybe a less intensive way of giving teclistamab is contributing to a better immune system and therefore a lower risk of infection. 

Another contributing factor to the flattening of infections over time is the fact that we now have a better understanding of what is the best type of prophylactic treatment for these patients, so we know better how to prevent infections. So we need to give patients herpes virus prophylaxis; we need to give these patients prophylaxis to prevent PJP, for example, with co-trimoxazole. I think what is very important is to give patients IVIG supplementation treatment as soon as IgG drops below 4g/L and we will have a a poster presentation at the next EHA meeting next week in Frankfurt, where we showed that IVIG supplementation treatment can substantially reduce the risk of serious infections. 

What is the clinical impact?

So teclistamab is now approved based on the results from MajesTEC-1 and the study results really support the use of teclistamab for patients with heavily pretreated triple class exposed or triple class refractory multiple myeloma. Next step is, of course, now that we have a very effective drug in heavily pretreated myeloma patients is to further improve the results. So ongoing studies are learning us more about combination treatment. For example, teclistamab with a CD38 antibody, teclistamab with another bispecific antibody, for example teclistamab plus talquetamab is also very efficacious in heavily pretreated multiple myeloma, as we learned during this ASCO meeting. 

We are bringing teclistamab to earlier lines of therapy, early relapse but also newly diagnosed patients and hopefully also newly diagnosed patients will benefit from the introduction of teclistamab, for example, as a maintenance drug after transplant or in combination with daratumumab or lenalidomide in the MajesTEC-7 study for patients with transplant ineligible disease.

We also had a poster here at at ASCO about prophylactic tocilizumab, so tocilizumab and IL-6 receptor blocker given before we start teclistamab and it's important that prophylactic tocilizumab was able to reduce CRS frequency from 70% to less than 30%, approximately 25%. Maybe prophylactic tocilizumab in a subset of patients will pave the way towards giving teclistamab outside of the hospital because now we have to hospitalise the patients during step-up 1, step-up 2, and the first full dose. Maybe in a subset of patients with prophylactic tocilizumab, we can give teclistamab in the nearby future outpatient, which is more comfortable for the patient and also saves beds so that we can use them for other patients.