In San Diego this year, ASH 2024, I was able to present on behalf of all the co-investigators the initial results of the safety run-in portion of the EMN30 MajesTEC-4 trial which is a very big, large, phase III randomised trial enrolling patients with newly diagnosed multiple myeloma who received either a triplet or a quadruplet induction therapy after autologous stem cell transplantation and who have achieved at least a partial response to receive a new modality of maintenance of fixed duration one, either teclistamab alone, the anti-BCMA bispecific antibody, or teclistamab combined with lenalidomide versus the standard of care, lenalidomide alone, for two years.
What we presented was the safety run-in testing the safety and efficacy of either teclistamab alone or the combination of teclistamab lenalidomide. So 90 patients have received the treatment until now with two different dosages of teclistamab. In cohort 1, the more intense schedule one, teclistamab was given weekly and then biweekly and monthly only after six months up to two years, while in cohort 2 and cohort 3 teclistamab was given immediately monthly at the dosage of 3mg/kg starting from cycle 2. So cohort 2 teclistamab lenalidomide, again together, while cohort 3 teclistamab alone.
What we showed by this initial result, of course the follow-up is not long until now. For cohort 1 it’s 21 months, for cohort 2 and cohort 3 it’s just 9 months. First of all is that the combination can be safely administered, and also teclistamab alone, with the most frequent adverse event being neutropenia. That is higher with the more intense dose scheduling of teclistamab and is lower when you are going directly to the monthly administration but it is mainly an isolated neutropenia, so without other haematological toxicity and not leading to treatment discontinuation. Another frequent non-haematological toxicity was CRS that was exclusively grade 1 and 2 and mainly related to the two step-up dosing and very, very rare after the first full dose and thereafter. As I said, this toxicity did not lead to treatment discontinuation.
The third important point regarding safety is that despite the use of teclistamab in the upfront setting, the infectious issue is there as well. So we had something around 30% of grade 3/4 infections that were mainly in the upper respiratory tract. However, these infections could be safely managed and together with the infection we observed hypergammaglobulinemia in approximately all the patients. So the recommendations are absolutely to go through the IgG replacement, that this is highly recommended and to put in place infection prophylaxis.
From the efficacy standpoint, we saw unprecedented efficacy results because 100% of the patients upgraded their response during maintenance, going from less than CR to CR and, most importantly, to minimal residual disease negativity with the sensitivity level of 10-5 as detected by next generation flow. All the patients, so 100% of the patients, at 12 months in cohort 1 and 6 months in cohort 2 and 3 were MRD negative. Of course, the analysis for the moment is not intention to treat because the population and the study is still ongoing, but it is in the evaluable patients, that is to say patients that had a baseline sample and at least one sample during maintenance therapy.
Currently, the randomised phase of the study is ongoing. We have enrolled something like 200 patients in more than 20 countries, 130 sites all over the world. So we’ll see results in the upcoming years and the primary endpoint of the phase III part of the trial is a dual one – PFS and CR MRD negativity rate at one year.
What is the clinical significance of these results?
The study, despite as I said preliminary results, clearly highlighted the potency of the use of the bispecific in the maintenance setting which is able to push the majority, let’s say, if not all the patients, into minimal residual disease negativity. This is highly [??] a fixed duration treatment, so two years, and in patients that are achieving at least CR teclistamab is held after one year. At the same time we also underlined the fact that we should always keep an eye on infection and that the infection [??] is part of the treatment with bispecific antibody.
