EBMT 2025 | Optimizing anti-CD38 monoclonal antibody-based quadruplet therapies in newly diagnosed myeloma

In this EBMT 2025 annual meeting, I had the pleasure and honor to share a session with Dr Mari-Vi Mateos from Salamanca in Spain about a very important, I think, and timely topic in the field of myeloma, namely the role of quadruplet combinations in the management both of the elderly population, but also the transplant-eligible population. And to make a long story short, I would summarize everything by saying, probably it should be at some point quadruplet for all. 

Based on the PERSEUS trial, I think it is now well-established, more and more widely used that the combination of daratumumab plus VRd, bortezomib, lenalidomide, dexamethasone is a standard of care for induction prior to transplant, and this has been validated in this so-called PERSEUS trial. And I think more and more people are using this regimen for induction. 

When it comes to the non-transplant-eligible population, in the last six or seven years, we’ve been living with some very nice results based on the MAIA trial, and daratumumab, lenalidomide, dexamethasone, proved to be an excellent and highly effective, well-tolerated regimen in the non-transplant-eligible population. 

The great news we had in the last, I would say 12 months, was about the release of the results of the IMROZ trial, the BENEFIT trial, and more recently, the CEPHEUS trial. These trials, in general, included relatively old patients, but they are usually fit, in general up to age 80. And these trials established the proof of concept of using an anti-CD38 monoclonal antibody, whether daratumumab or isatuximab, combined with VRd in this population. And there is a clear benefit in terms of MRD negativity, sustained MRD negativity, and this is translating into a significant benefit in terms of progression-free survival. And this is really great news because for the first time, we are doing better than the Dara-Len-Dex combination. And thanks to the IMROZ trial, for instance, we have now the Isatuximab-VRd regimen approved and more and more widely used. 

Very recently, around mid-February 2025, we’ve seen the publication of a Phase II trial, an academic trial from Norway called the REST trial. And this is very interesting because this trial tested the same combination quadruplet, isatuximab-VRd, in the elderly but maybe frail population. And in order to use this protocol, actually, this regimen, they have actually modulated the dosage of dexamethasone, and dexamethasone was skipped after two cycles. And it proved to be effective. and you have almost 40% MRD negativity. 

So in another word, I would say, based on IMROZ, based on BENEFIT, based on CEPHEUS, and now with the advent of the result of the REST trial, one may envision that we should use a quadruplet anti-CD38 VRd to everybody. And then in some population who are very old or frail, we may do some adjustment, a sort of a quadruplet light regimen. So you can see, I think we’re making amazing progress in multiple myeloma, whether in the transplant or non-transplant-eligible population.

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