COMy 2025 | An EU perspective on the treatment of advanced relapse in myeloma beyond immunotherapy

There is an ongoing revolution in multiple myeloma, particularly in advanced relapses. Immunotherapy is now the backbone for patients fit and in some way that need the best effectiveness as possible according to an endpoint of an MRD negativity status, that is the mission that we have with the best patient in terms of performance status and in general with the young age in which we want maybe to correlate with the cure of our treatment. And in the same time we are going also to revolution the management of every patient beyond immunotherapy and in this patient we have several options that have become available. One of them is selinexor that we use in combination with bortezomib and dexamethasone according to BOSTON trial from second line of treatment. And we have seen excellent subanalysis in patients that are proteasome inhibitor-naive and particularly when used in second line. 

In my idea and my clinical experience, the toxicity is not a problem if prophylaxis is adequate. If we in some way balance the need of our patient according to a very good compliance to a tolerability that is also related to a drug that is orally available with bortezomib that is a subcutaneous drug, I think that selinexor can be used in a wonderful way after daratumumab, lenalidomide, dexamethasone and in general in len-refractory patients. Let’s not forget that we can use selinexor as a single agent according to the STORM trial in a heavily pre-treated population. I think that in this setting the idea of having the possibility of disease control with an oral drug is something that we really have to care about. Particularly if we consider that this drug is really fast in its action and we can in some way control in a domestic setting, in heavily pretreated, is something that we really need. 

Another really important drug that has been available also in my country, in Italy, is melflufen, melphalan flufenamide. This is a new concept of chemotherapy, the idea of having a chemotherapy without any great toxicity, really personalized, really focused on the myeloma plasma cells, And I think that is another wonderful idea for heavily pretreated, the frail population and also for the ones that have not so excellent logistic, because this drug is possible to be one monthly administration, every 28 days, fixed dose with a very good compliance due to absence of relevant adverse events. I think that for a disease control this can be considered, but I think that we are going to discover other use of the drug and this can be also a wonderful bridge to new immunotherapies and in general can be useful for patients that want a period of more relaxed and more comfort according to a very good schedule. 

So I think that selinexor and melflufen are for sure drugs that we are able to use, waiting for the positioning of other drugs and of other combinations also based on these drugs. We know that there are ongoing trials EMN29 that is going to combine selinexor with pomalidomide. This could be another ideal triplet that can be used also in a representative setting, and I’m curious to see also more data potentially also from real-world where it could be possible of melflufen in other combination. I know that there is not in this moment clinical development but the idea of combining the melflufen with bortezomib, so a proteasome inhibitor, in the idea in general also with the combination with daratumumab, the idea of potential rechallenge with this drug according to ANCHOR and LIGHTHOUSE clinical trials are something that we should explore more, waiting for the future. And I think that is really important to care also about everything that the patient, because in this moment we need to understand which is the life after immunotherapy or without in the one in which there are contraindications to use bispecific antibodies and CAR-T.

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