ASH 2025 | Classifying and managing high-risk smoldering myeloma: current and future approaches

Okay, I think nowadays there is quite a controversy about… not how to treat; I don’t think there is a controversy about how to treat high-risk smoldering – it’s mainly the controversy about what are the most accurate parameters in order to identify the high-risk populations. Until now, there had been two classifications; the major classification was the Spanish PETHEMA classification. Now we have agreed that a 2-20-20 classification probably is the best one: to have more than two grams per deciliter of paraprotein, to have more than 20% plasma cells in the bone marrow, and a free light chain ratio of more than 20. And if you have two or three of these criteria, you have already a 50% risk of progression at two years. But on top of this, we can calculate the exact score based on this classification because it’s not the same to have 20% plasma cells or to have 40%, or a free light chain ratio of 20 or a ratio of 50. As you can imagine, the risk is different. And we have established the score, and patients having a score above 9 or 12 have, by sure, more than 50% risk of progression. 

On top of this, you should evaluate the evolving pattern, also the cytogenetics, also you should look for pure genomic, also for MRI in case there is already one focal lesion. And if you put all this together, plus the circulating tumor cells that we can discuss later on, if you put all this together, you can calculate for the patients more accurately what is the risk of progression, 50% or 80% in two years. And according to this information, you can share it with the patient, and the patient should make the final decision together with the doctor. 

Regarding treatment, as you had mentioned, daratumumab has been approved, but probably this is not going to be used as the standard of treatment because how are we going to treat the high-risk smoldering patients? I think they are going to be treated, according to it, exactly the same as active myeloma patients. In other words, if you have in front of you a patient that has a really high risk of evolution into active myeloma and is not a transplant candidate, probably you will move for a quadruplet instead of a single agent. We used lenalidomide in the past; now daratumumab has been approved, but probably the next step is to use the quadruplet. Or alternatively, to use a bispecific antibody or a CAR-T, we have already preliminary data from the Boston group and from our group that the use of bispecific antibodies as well as CAR-Ts are extremely valuable in the high-risk myeloma patients. 

Regarding the transplant patients, we will go in the same direction. In fact, the CESAR trial that we conducted in 90 patients has shown beautiful results with high rates of minimal residual disease. However, we realized that still patients have biochemical relapses frequently, and we decided, and this was presented at the recent ASH meeting, in order just to try to avoid moving from biochemical into a clinical relapse to introduce the concept of early-risk intervention. And this concept of early-risk intervention was based on the use of daratumumab, pomalidomide, and dexamethasone. From the 43 patients with biochemical relapse, we treated with DaraPD 29 patients. The other 14 patients prefer not to be treated at this moment. And I can tell you that the vast majority of the patients responded to treatment. Overall response was 90%. The complete response was 50%. And the time to progression of 50 months was 95%. Nevertheless, I can also mention that there were also some biochemical progressions also under DaraPD; the time to biochemical progression at 50 months, the proportion was 74%. 

Therefore, what is my message? My message is that the concept of early risk intervention in order to avoid the possibility of having CRAB symptoms is well established and is very attractive, but for me what is most attractive is to use the treatment that could eradicate the disease by the decision of intervening in the high-risk smoldering myeloma patient at the time of diagnosis.

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