Importance of MRD in newly developed multiple myeloma
Prof Xavier Leleu - Poitiers Centre Hospitalier Universitaire, Poitiers, France
Is the depth of response clinically relevant in multiple myeloma?
Absolutely. Multiple myeloma is a chronic disease, is a disease that we cannot cure yet, and the depth of response is absolutely key because it has been largely demonstrated that it was a surrogate to survival and that the deepest response you could get, and I could even add the earlier you get to that deepest response, the more likely you will have a prolonged survival, even continuing the treatment. So, definitely, the depth of response is key which is why the FDA has recently in the ODAC in April 2024 actually validated that MRD negativity rate at least at 10-5 plus complete response could be a primary endpoint of studies for registration in the US.
Should achieving MRD- be a treatment goal for NDMM patients?
Absolutely so, particularly in clinical trials, in drug development and in research it is important. In routine life I would say it’s not yet ready for primetime and it is not yet ready for primetime because you could always perform the MRD and then explain to the patient the results but right now it is fair to say that you’re not going to adapt your treatment based on the results. Therefore, at least in Europe and for us in France, we systematically perform this MRD assessment in patients that are studied or treated in the context of clinical trials, of research trials. In real life we do not recommend to do that MRD because besides just describing the results to the patients, the patient will then ask to you what’s next. There are studies ongoing and we don’t have yet the results of what to do with the results. So not for real life yet but definitely systematically for clinical trials.
What is the clinical relevance of MRD and PFS in clinical trials for NDMM?
The relevance is absolutely key because the survival of the patient now has improved incredibly. In young patients that we call transplant eligible, TE patients, newly diagnosed, we think that the survival without relapse, the median survival without relapse, will be probably around ten years, maybe 12 years, on the basis of an incredible study recently presented called PERSEUS. In non-transplant eligible, in transplant ineligible patients, though there is no transplant still we saw with IMROZ and I hope with BENEFIT we’ll be able to replicate that the median survival without relapse is going to be around eight to nine years.
So the thing is that for the patients, for their families, it is very important to have an earlier timepoint. Wait ten years to know if you’re a good patient, if you have good myeloma or if you have not a good myeloma, is difficult. The patients, the families, they want something a bit much earlier but still scientifically sound. Something that is important for us and that tomorrow we’ll be using to drive the treatment. We know we can’t do that yet but clinical trials are ongoing and that’s exactly what MRD is about.
MRD is an early timepoint which will help the physician and the patients know better about the real prognosis, the real benefit from the treatments and whether a treatment change should be applied and not wait ten or 12 years to change the treatment and to have had all the safety profiles issues and potentially not great benefit from the treatment. So MRD is absolutely key and that’s why it’s great that it correlates with survival. It’s an early endpoint really to help the patients and the physician think about should I adapt my treatment or should I not.
So I appreciate that we are not there yet to say how we can adapt but, again, there are ongoing clinical trials to answer that question.
Are there any other important abstracts at ASCO 2024 regarding NDMM that you would like to talk about?
Yes, absolutely, there might be a couple of them. There might be a consequence, really minimal but a limitation still, to this incredible development we have, developments we have, with the quadruplet-based regimen in newly diagnosed myeloma is that we really put… I guess you have a saying in English which is all the eggs in the same basket or something close. Looking at everyone shaking positively looks like I’m good here. So we really put all our eggs in the same basket – it’s manageable to the patient, it’s safe enough, it’s incredibly effective, lovely. Sadly, it won’t cure all the patients; sadly, some of the patients still have a terrible myeloma and some of the patients will relapse early. The benefit for some of the patients will not be as good as for the others.
The problem of these patients is that since you have been giving all the drugs, almost, at once in one regimen up front, how are you going to rescue these patients in the relapsed setting, in second line, when they will be relapsing? Knowing that their myeloma is tough to treat because they did not benefit to the same extent with the four drugs as the other patients. So we need a new family of drugs, different mechanisms of action, new targets. Isatuximab is a CD38 targeting immunotherapy. We need new immunotherapy with a different target and for the past two, three, four, five years, I would say two to five years, there has been a very interesting target called BCMA.
BCMA maturation antigen which is on the plasma cells, on the tumour cells, that has been developed, studied and targeted with new immunotherapy, CAR T-cells, which we call cellular immune therapy, bispecifics, antibody based, let’s say, protein antibody based immunotherapy, and a new concept we call ADC, antibody-drug conjugate that GSK pharma company has developed in the series of studies, the DREAMM studies. The name of the drug is called belantamab mafodotin, it’s a BCMA-targeting immunotherapy and when it attaches to the receptor on the tumour cells it allows in the tumour cells a chemical compound, the mafodotin. It’s a completely different mechanism of action so it’s great because the tumour cells can be fooled by the different mechanism of action compared to other regular immunotherapies we use.
We have demonstration, it has been presented, now it will be presented at ASCO, two studies, two phase III studies for registration from GSK – DREAMM-7 and DREAMM-8. So two studies use belantamab mafodotin in combination compared to a standard of care now in the relapsed setting, we are not in newly diagnosed anymore, we are in the relapsed setting. The two studies will demonstrate that you can probably rescue patients that have had this regular CD38 immunotherapy up front with this new mechanism of action ADC targeting BCMA in the relapsed setting. This is great because it’s exactly what we need to develop now. We have incredibly improved the up front setting but for some of the patients who will not benefit to the same extent we need to improve the relapse, first relapse, second-line setting to make sure we can salvage these patients with new drugs, new mechanisms, new targets. That’s exactly what the belantamab mafodotin and the DREAMM-7 and DREAMM-8 study are about.
DREAMM-7 has been presented in virtual ASCO some weeks ago, DREAMM-8 will presented tomorrow as a late-breaking abstract for the first time at ASCO 2024. The two studies are positive so there’s great hope that the drug will be available in the different countries, in different continents, and I hope will be reimbursed and particularly in Europe because it’s a difficult continent for the pharma companies to get the drugs approved and reimbursed. I hope we’ll be getting access to this drug for our patients in my country.
