ASH 2025 | An overview of promising therapeutic approaches being explored in newly diagnosed and R/R myeloma

In last years we have seen a great diagnostic and therapeutic revolution in multiple myeloma. Starting from frontline setting in which we have seen in transplant eligible outstanding data from PERSEUS with the potential progressive survival until 17 years like we have seen in last EMN conference. But also in transplant ineligible, we have seen incredible data from IMROZ in which we can see also there that MRD negativity is not anymore a scientific idea, but has become the real end point in order to obtain the deepest response and the potential in the future to stop the treatment and to really cure multiple myeloma. However, new drugs are being investigated, also in frontline setting, such as linvoseltamab, a new generation anti-CD3xBCMA, bispecific antibody with outstanding data as monotherapy in both transplant eligible and not eligible. And there is also an interesting study, COBRA study, in which KRd is compared with VRd, with the idea that new generation proteasome inhibitor could have a sense in particular settings of patients according to the deepness of response and according to the quality result that this study is going to show. 

In the relapsed/refractory setting, the most important data that has been presented here in Orlando is MajesTEC-3, the combination teclistamab, B-specific antibody, anti-BCMAxCD3, together with Daratumumab, without dexamethasone. Dexamethasone is done only in the first part of the study, then it is a dexamethasone sparing regimen, so this in some way correlates with high quality of life and high tolerability for our patients. The control arm is the best standard of care, so Dara-PD or Dara-VD, and the data are absolutely outstanding in terms of progression free survival and MRD negativity, even if in the first part the regimen is a little bit toxic, we know that it has started in 2021 when we had no capability to manage bispecific antibodies like we have today. There were no guidelines, no recommendations, but today we know that with intravenous immunoglobulins and in general with the replacement with antibiotic therapy, bispecific antibodies are more feasible than in that time. However, at the long term, the regimen is really well tolerated and the response arrived to show quite a plateau. So this can be considered in potentiality as a new standard of care starting from second line of treatment. 

Other interesting data are from etentamig, a phase one study with this new bispecific antibody, anti-BCMAxCD3 in combination with pomalidomide, deep response, interesting synergism between the two agents, and also very good tolerability. Etentamig is really well tolerated. I have participated as investigator to this trial, and I can see that Etentamig is one of the best specifics that are arriving. Let’s also consider that new regimens are arriving, but I think that CARTITUDE-4 confirmation of data is something really interesting. Antio-cel showing overall response rate confirmed over 97% is another incredible data, and we are going to see other molecules, such as a new interest in CAR-T, KLN-1010, seen in MMI CAR-T study, in which we can see outstanding data in an in-human study in which we can see a very good effectiveness together with an incredible tolerability thanks to the not need of lymphodepletion for our patients – so this is another important point for this study. 

KTX1001 is an NSD2 inhibitor, really interesting particularly, particularly for the capability to, in some way, cure patients with the translocation 4;14, but not only. In the study, the population is with all the potential cytogenetic characteristics, and data really encouraging for potential new phases of the study, and also potential combinations that are ongoing, such as the one with the mezigdomide. The future is showing also new mechanisms of action and so potentially new combinations that we can see also at the long term in the next conferences, so this is something encouraging for patients that are not showing any response or that are losing the response to the drugs that we have currently available. 

Let’s not forget that we are going to see also interesting data from international registries such as Oneur, Preamble, in which we are going to see some characteristics of patients in which we have some unmet medical need, data from potential sequencing and in general also data for the drug withdrawal. We have to understand in which patient we can stop the treatment and in some way only monitor them. MRD negativity will be the driver and sustained MRD negativity will be the potential end point that we have to reach in the next future, particularly in younger patients. And I think that data from real-world registries will help us to drive as best as possible our choices. All these novelties to confirm that the cure of multiple myeloma is not so far anymore, and this is the best wish that we give to our patients, to their caregivers, and to all myeloma researchers.

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