EBMT 2020 | Therapeutic options for hard to treat R/R myeloma

During this EBMT 2020 virtual meeting, I had the privilege to discuss the treatment of a hard to treat myeloma patient. And actually this are the relapse refractory patient. These are patients who have usually failed the most common therapeutic options, namely proteasome inhibitors autotransplant IMiDs. And this is where you need some novel options. And here particularly we discussed the issue of patients who are lenalidomide refractory. And this is really becoming a matter of concern because lenalidomide is increasingly used as maintenance therapy after autotransplant until progression. And it is also more and more frequently used as the frontline treatment in the non-transplant elderly population. And in both scenarios, we are more and more faced with patients who are refractory to lenalidomide. Therefore, one needs to design new options, new combinations and new protocols for these patients.

Actually to make a long story short, there are different options emerging. The CANDOR protocol, phase three randomized trial just published a few days ago. And this trial has compared daratumumab, carfilzomib, dexamethasone versus carfilzomib, dexamethasone. And it is a very attractive option because this triple combination proved to be superior to the doublet combination with carfilzomib, dexamethasone. And in those patients who are lenalidomide refractory, this is very interesting because you are using a monoclonal antibody an anti-CD38 daratumumab with a different mechanism of action. And you are using a second generation proteasome inhibitor carfilzomib. Then you have a combination of drugs which can allow to overcome lenalidomide resistance.

This is also true for another exciting trial, the IKEMA trial which had a similar design roughly, comparing isatuximab, another anti-CD38 antibody combined with carfilzomib and dexamethasone versus carfilzomib, dexamethasone. We have roughly similar results showing that this triplet combination of isatuximab, carfilzomib, dexamethasone is superior to carfilzomib, dexamethasone alone. This is also another option for these lenalidomide refractory patients.

Of course, one may ask the question why not use another IMiD and the best candidate would be pomalidomide. And we know that although one may suspect some cross resistance between different IMiD drugs, still pomalidomide has been shown to be able to overcome resistance to lenalidomide. And here we can end up with several combinations like isatuximab, pomalidomide, dexamethasone. This is the spirit of the ICARIA trial, and the results are also extremely appealing. The study has been published in The Lancet, so I will not go into the details.

We have also daratumumab, pomalidomide, dexamethasone, another attractive option. Phase two data already published, the phase three results, hopefully to be released in the next few months. But also the OPTIMISMM trial already published with PVd, pomalidomide, bortezomib, dexamethasone. Although this is a relatively old combination, still, the results are interesting. And that brings me to the option of keeping bortezomib a first-generation proteasome inhibitor. And that is the CASTOR trial daratumumab, bortezomib, dexamethasone.

In summary, we can see now, while this has been viewed as a very difficult and challenging situation, the lenalidomide refractory myeloma patient. Actually now we are having some very important, highly effective new options. Namely, in my opinion, the combination of anti-CD38 antibodies plus a second generation proteasome inhibitor like carfilzomib.