Teclistamab Combo Yields Deep Responses in Newly Diagnosed Myeloma
Marc Raab, MD, PhD, discussed the MajesTEC-5 trial of teclistamab plus standard myeloma therapies in transplant-eligible newly diagnosed multiple myeloma.
Marc Raab, MD, PhD
The MajesTEC-5 trial (NCT05695508), a phase 2 study evaluating teclistamab-cqyv (Tecvayli) combined with standard myeloma therapies in patients with transplant-eligible newly diagnosed multiple myeloma, demonstrated promising safety and efficacy, with 100% complete response (CR) rates and 100% minimal residual disease (MRD) negativity (10-5) after 3 cycles.
The standard myeloma therapies patients received with teclistamab were either daratumumab (Darzalex) plus bortezomib, lenalidomide, and dexamethasone (Dara-VRd), or daratumumab plus lenalidomide and dexamethasone (Dara-Rd).
While safe, expected toxicities like infections were observed and manageable with intravenous immunoglobulin (IVIG). According to Marc S. Raab, MD, PhD, future studies will focus on randomized trials to confirm these findings and explore teclistamab's role in maintenance therapy and non-transplant eligible patients.
In an interview with Targeted OncologyTM, Marc S. Raab, MD, PhD, medical director of the Heidelberg Myeloma Center at the University of Heidelberg in Heidelberg, Germany, discussed the MajesTEC-5 trial of teclistamab combined with standard myeloma therapies in transplant-eligible patients with newly diagnosed multiple myeloma.
Targeted Oncology: Please provide an overview of the MajesTEC-5 trial and its primary end points.
Raab: The MajesTEC-5 trial is a phase 2 trial, mainly focusing on feasibility and safety, and as further end points, on efficacy, of course, in terms of how to implement a bispecific, namely teclistamab, a BCMA CD3 bispecific T-cell engager, in frontline therapy in myeloma for transplant-eligible patients. We combined this with standard of care drugs, like PERSEUS [NCT03710603]-based with Dara-VRd or Dara-Rd without bortezomib. So, 2 cohorts, plus or minus bortezomib, and we have now finally concluded the induction therapy.
Microscopic photorealistic image of myeloma cells - Generated with Google Gemini AI
What updates were presented at the 2024 American Society of Hematology (ASH) Annual Meeting and Exposition, and how do they build upon previously published data?
The baseline for us, of course, is PERSEUS, which is the Dara-VRd combination regimen induction therapy, which just has been not only published, but also approved by the FDA and [European Medicines Agency]. We now wanted to add teclistamab bispecific to this backbone. What we see is, both with bortezomib as well as without bortezomib as a quad, as well as a 5-drug regimen, is that it is feasible.
The toxicity that we observe is what we usually call manageable, but what is also expected in terms of knowing the single drugs, one after the other and now combined. We see an infection rate which is not higher than expected based on the use of teclistamab, even as a monotherapy in late lines.
But we also wanted to build upon our idea that T-cells that have not been exposed to any therapy before, because we are here talking about newly diagnosed patients, are very effective, and that is what we see, a very effective regimen we have in those patients who have completed the induction therapy. We have a 100% complete response rate. So, all patients achieved a complete response rate, and in all patients tested so far after 3 cycles. So, it is a 6-cycle induction regimen, but after 3 cycles, already we have all patients tested so far in MRD negativity, 10−5 based on flow cytometry, which I think has never been seen before to this extent.
What have been some of the most significant safety concerns observed in the trial, and how can oncologists effectively manage these in clinical practice?
As expected, we see infections, as we know with BCMA bispecifics. We do see a rate of grade 3/4 infections, which is in the similar range as expected if you add or if you supplement IVIG, so immune polyvalent immunoglobulins, to mitigate the very severe infections. This is basically what we can do and what we can recommend to really do this as always, if we use a BCMA bispecific. The other more rare but noticeable toxicities were rash, mainly when we added lenalidomide as of the second cycle. The first cycle was teclistamab and daratumumab only, which is kind of explainable by the immune reaction that you again support by doing so. What we also saw in some patients, though that's more in most cases a laboratory finding, is that we see lipase increase, but it is also, if we feel, that is important to note, if you later come across this kind of laboratory findings. We had only one patient with mild pancreatitis-like symptoms and the lipase increased. All the others were asymptomatic.
How might the findings from this trial influence future treatment guidelines or clinical practice for patients with relapsed, refractory multiple myeloma?
It is a phase 2 trial, so it is mainly based on safety and some efficacy data. It is not a randomized trial, so we will not be able to get a new label on this for this combination therapy. However, we certainly have data that strongly support the [approval of] teclistamab or a bispecific in the first line, in combination, even with 4 drugs, but certainly with 3 other drugs. So namely, Dara-Rd in our case, for a highly effective treatment in transplant-eligible patients in induction therapy.
How might future studies build upon this trial to further refine treatment strategies?
What we actually are already discussing is a randomized trial to build upon the phase 2 trial that we are now running and presenting for the first time, so that we can really prove that in a randomized fashion, the addition of teclistamab, in our case, to the standard of care, so Dara-Rd at least, will further deepen response rates in terms of MRD negativity, and for sure, in terms of sustained MRD negativity, because the MRD negative starting point in our trial, in our results, is already after 3 cycles in most cases. That means the starting point for sustained MRD negativity starts very early, so we expect to have a very high rate of sustained MRD negativity, which is probably the future goal in myeloma therapy, as this has been shown by many now to be highly correlated with a very long progression-free survival and hopefully overall survival, of course.
Are there any additional trials or upcoming studies exploring teclistamab or similar therapies that you think oncologists should be aware of?
MajesTEC-4 [NCT05243797] is evaluating teclistamab in maintenance therapy after transplant, there's MajesTEC-7 [NCT05552222], which is kind of our sister trial, but already in a phase 3 where teclistamab, in combination with [daratumumab, lenalidomide, and dexamethasone], is explored in non-transplant eligible patients, so the usually more elderly patient, and also the first data have been presented at [the American Society of Clinical Oncology Annual Meeting] and I think will be updated at ASH this year, have been also showing important, promising results, also in terms of response rates and depth of response, namely MRD.
