In the current study presented at ASH 2020 I gave the final results from a single arm phase II trial for newly diagnosed multiple myeloma patients treated with the four-drug combination of carfilzomib, lenalidomide, dexamethasone and daratumumab. The carfilzomib drug was given on a weekly schedule with 56mg/m2, so weekly KRd-D if you want. The study has enrolled a total of 41 patients per the study protocol; patients have received a total of eight cycles of combination therapy. The study had traditional inclusion criteria – relapse and performance status and so forth.

Because the study includes eight cycles of this combination therapy and then the study is over with the primary endpoint set as MRD negativity therefore there is no exclusion if patients choose to not go for a bone marrow transplant or if they are not even a candidate for bone marrow transplant. As long as they are eligible to go on the trial they could go on the trial so patients who were slightly older could go on if they had a good performance status and good lab results.

For patients who are fit and potential candidates for a transplant, they would be advised to collect stem cells after 4-6 cycles on this protocol. Again, the primary endpoint was to see what is the MRD negativity rate after a total of up to eight cycles and this is in the absence of a bone marrow transplant.

How did you evaluate the efficacy of this method?

The primary endpoint for the study, as I mentioned, was to look at MRD negativity after a total of up to eight cycles of weekly KRd-D and this is in the absence of a bone marrow transplant. We used the traditional ways of assessing clinical responses with the IMWD criteria and that includes also the bone marrow assessment for MRD negativity. We used in this study parallel ten-colour single tube flow cytometry as well as VDJ sequencing to determine MRD negativity.
For practical purposes the study used the flow cytometry for all the patients because that was done for each and every patient. The sequencing was done for the majority of the patients. The results were very consistent, they were identical for the two assays. We have actually just published a paper in another journal, it just came out some weeks ago online, where we evaluated several hundred patients at our centre with the two methods that I’m referring to and we show extremely high concordance. There is a 99% concordance between the two methods in our hands.

What were the key results?

The key results of this study, again based on the primary endpoint being MRD negativity after up to eight cycles, were quite striking. I would say these are unprecedented results. We show that 71% of the patients achieved MRD negativity after up to eight cycles of weekly KRd-D. If we look at other studies that have recently been presented and published we see that these results are very, very strong.

So, for example, the GRIFFIN study that was recently published in the Blood journal after six cycles of the VRd regimen and a bone marrow transplant they achieved in the intention to treat analysis 20% MRD negativity set to 10-5 negativity. In the other arm of the GRIFFIN study they gave six cycles of VRd daratumumab and a bone marrow transplant and in the intention to treat analysis they achieved MRD negativity in 51% of the patients. So VRd-D six cycles and transplant 51%; in the current study, single arm, it’s not the same study so patients may not be the same and there are a lot of other differences, I’m sure, but nevertheless after eight cycles of KRd daratumumab without bone marrow transplant we found 71% MRD negativity set to 10-5, the same. So I think these results are very, very strong.

There are additional presentations at this ASH that highlight the importance of MRD in the newly diagnosed setting. To me, the IFM2009 follow-up study that will be presented as an oral showing that at eight years of follow-up MRD negativity is the strongest predictor of outcome. They also show and they discuss that there is no survival benefit of transplant in the upfront setting. In the conclusion of that abstract the authors say that with four-drug combinations being implemented in the future most likely very many patients could achieve MRD negativity and the utility of transplant could move to a delayed use of melphalan and stem cells if needed. I think that is probably where the field will be going.

What is the clinical impact of these results?

It is always hard to predict the future and we have many times been wrong but I think when it comes to the multiple myeloma field in the newly diagnosed setting looking at powerful combinations and MRD assessment, there are now so many studies. So if we were to guess where the field is going it’s mostly likely going to be somewhere in the direction where the majority of the studies are. So if I just look and see the IFM2009 study with eight years of follow-up presented at ASH 2020 showing that there is no added benefit of transplant if you use combination therapy that’s effective. That’s what they show – VRd /- transplant, no survival difference. Then you look and see the four-drug combination achieving very high rates of MRD negativity, you can do the VRd-D with transplant with 51% or KRd-D without transplant we showed 71%.

I think it’s very likely that patients could be treated with these powerful combinations achieving MRD negativity and collect and store the stem cells and have them as a back-up. Still the transplant would be a valid option if you don’t have access to all these drugs. There are many countries where you don’t have access; transplant still is the most powerful option so therefore that should be used. And for patients who don’t have a great outcome with these new drugs transplant still plays a major role.

But the big shift, I think, will be the implementation of MRD testing and the option of delayed transplant for patients who have a great response to the new drugs. That’s what I think and I think maybe additional antibodies could continue to stir up and maybe get rid of some of the other drugs. Maybe it’s going to be all the antibodies in the future, we’ll see.