EMN 2021 | Latest developments in the treatment of smoldering myeloma

The treatment of multiple myeloma is changing in the recent years. In 2014, we have started calling multiple myeloma cases that were before labeled as asymptomatic just because we learnt that these cases would progress to active multiple myeloma very likely in the next two years, 80% of them would. And it was decided that these patients would be better off treated than managed expectantly.

Since then, what’s left of smoldering multiple myeloma nowadays is, I would say, staged as low-risk, intermediate-risk and high-risk of progression. And the question is now whether we can improve survival of patients by treating at least the high-risk smoldering myeloma cases. So, I would say that the first advance in smoldering myeloma treatment comes from prognostication. We need effective prognostic scores to identify people at higher risk of progression and we consider a high-risk of progression, patients that would progress with a 50% chance in the next subsequent two years.

So in these patients, there have been studies which demonstrated certainly progression-free survival benefit of the treatment arm as compared to the observational arm. So, there has been now quite a strong debate on whether findings from these studies, some of which both are translated into an improvement in overall survival, so whether these studies should translate into a change in current practice even in routine patient care.

There has been some resistance into adopting these studies in real world. And of course, resistance is based on some fairly mature, I would say, survival data and the worry that the sooner you start treatment, the sooner you may actually select chemoresistant clones and therefore a hamper at the future treatment lines of these patients. So, I would say that the most mature studies that have been presented so far, are based on lenalidomide either alone or in combination with dexamethasone.

And as much as the studies have clearly shown that progression to active multiple myeloma can be delayed, and there is a benefit of that, of course, because the patient will likely never develop renal failure, osteolytic lesions, and therefore, the quality of life is certainly improved as much as the progression-free survival is. We believe that these studies don’t actually, I would say, take advantage of the full potential of novel treatments in multiple myeloma.

So, of course these studies suggest an option for high-risk smoldering myeloma patients, but I personally look with great curiosity to a very much different and more radical approach to a smoldering myeloma treatment. This different and radical approach is a curative approach, which has in mind the question whether, by treating early, we can treat a less complex disease and therefore we may achieve cure by treating patients earlier.

Lenalidomide cannot guarantee this, actually it is highly unlikely, whereas there are studies like the GEM-CESAR trial from the Spanish group and carfilzomib, lenalidomide and dexamethasone, which is based in the US. These studies have shown impressive rates of overall response MRD negativity and of course progression-free survival. Overall survival data are less mature, but those will be important to understand whether a radical high intensity treatment approach for smoldering myeloma has the chance to change the natural history of the disease more profoundly than lenalidomide-based trials. So, it’s still out there to be discovered. I personally don’t treat high-risk smoldering myeloma patients outside of clinical trials, but this is very likely to change in the coming years.