COMy 2025 | The management of smoldering myeloma: key trials and the importance of risk stratification

The management of smoldering myeloma is changing in last years thanks to the wider availability of clinical trials. In general we have to discuss about who is today the high-risk patient because preventive treatment are for this category of patients. We continue to use the brilliant 20/20/20 evaluation from PETHEMA group in which we know that high-risk has seen a lot of clinical trials in last years but starting from QUIREDEX, in which lenalidomide and dexamethasone was superior to observation and now we have more than 15 years of expectations from this trial but let’s not forget that we have now also data with anti-CD38 daratumumab, the AQUILA study, has shown a superiority also versus observation study. 

In general, I think that we are strongly waiting for results of other trials such as Ithaca, Isatuximab, Lenalidomide and dexamethasone versus len-dex, in which I was really proud to be one of the investigators involved and let’s wait also for the bispecific antibodies. There is ongoing EMN34 with elranatamab, a Phase II, in which we are also treating our patients with brilliant results, really fast response and deep response. 

Another eternal question is not only to treat or not to treat, in my opinion, absolutely to treat the high-risk. The other question is how we can define today a functional high-risk in this patients and we should maybe include the biology and for sure the genomic pattern of our patient a new generation imaging. We study every patient with PET-CT plus full body MRI in order to detect also pre-lesions that is really important because the tricky point is not to undertreat but also not to overtreat our patient and this is another really important point. Moreover the next future will be to understand if we should treat only high-risk or maybe also low/intermediate smoldering high-risk. Some drugs are being placed for clinical trials also in this setting. For example linvoseltamab we will have a clinical trial with this drug covering all the smoldering and also high-risk MGUS. My idea is that the end point is another important thing to solve and the end point for the smoldering myeloma should be MRD negativity, because in this case we should aim to eradicate the clone, to cure the patient. And this is the best wish that we give to all smoldering myeloma patients, to their family, and to all myeloma researchers that are fighting against also pre-myeloma status and not only symptomatic myeloma.

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