The DSMM-XX, GMMG-HD10 or MajesTEC-5, it has three names, is a phase II study that explores the addition of teclistamab, the BCMA/CD3 bispecific antibody, in frontline newly diagnosed patients who are transplant eligible. This is a combination of teclistamab with standard of care, normally daratumumab-lenalidomide-dexamethasone or daratumamab-lenalidomide-bortezomib-dexamethasone. However, the dexamethasone is only invested as two cycles and bortezomib in one cohort is weekly given.
The idea of this study is to explore and leverage on the hopefully and practically very potent T-cell activity of T-cells that have not been exposed to any therapy before in newly diagnosed patients to hopefully deepen response and achieve MRD negativity early on as we know that although triplet therapies in the last few months and years have dramatically increased and prolonged PFS for patients, there’s still room for improvement because MRD negativity, even after transplant, for example, is only about 50-60%.
What was the study design?
The study design is a multicohort study. Basically, to simplify the [??] we have two main cohorts, one with teclistamab together with lenalidomide and daratumumab and the other cohort is teclistamab with lenalidomide, daratumumab and bortezomib. All of those patients have been sectioned in these cohorts; this is done in a 6-cycle induction therapy followed by stem cell transplant, high dose therapy and stem cell transplant, followed by up to 18 cycles of immunoglobulin therapy maintenance.
It’s a feasibility study so the main focus is, of course, safety, side effects, infections, CRS and so on, as with all bispecific antibody therapies, and, of course, also looking at efficacy.
What were the results of this study?
Of those patients who have completed already the six cycles of induction therapy, which is about 50% of the patients, all patients have achieved a complete remission. We have efficacy data after three cycles for all patients and so far all tested patients, we have three patients where we don’t have a sample after three cycles, but all other 46 patients have achieved MRD negativity already after three cycles measured by FLOW at the level of 10-5.
In terms of safety, we do not see any surprise in terms of infections or other side effects, knowing all individual drugs quite well because they are all approved, at least in second line. What we do see is grade 3/4 infection so far of about 35%. However, we have not seen any grade 5 infections, probably due to a very strict implementation of prophylaxis, namely antibiotic prophylaxis, at least for the first three cycles is strongly recommended as well as the supplement of immunoglobulins, mainly IVIgs, as soon as hypergammaglobulinemia, which was basically present in all patients as [??].
In terms of follow-up, of course, for PFS have data for now for induction therapy part.
What do you think is the clinical significance of these results?
As I said at the beginning, early achievement of MRD negativity is certainly so far the best prognostic marker for a longer PFS or a long PFS. As I mentioned earlier, compared to the best available therapies, which is quadruplet induction therapy with a CD38 antibody and lenalidomide, bortezomib and dexamethasone, we have in those few patients so far but we seem to have a signal that we have a much higher and much earlier MRD negativity rate already after three cycles and confirmed for our patients with [??] cycles of induction therapy.
So this might lead to a new standard of care regimen, once in a bigger randomised trial confirmed, where we see patients achieving across the board MRD negativity already in induction therapy, potentially looking at opening the avenue for limiting the duration of therapy, especially in [??].
Is there anything else you would like to add?
Of course I want to thank all our patients, their families and very much so my co-investigator and co-PI, [??], and the great collaboration between the GMMG study group and teclistamab study group, the two major German study groups.
