Investigating KRd versus KTd in NDMM patients with high-risk cytogenetics

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Published: 13 Jun 2020
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Prof Heinz Ludwig - Wilhelmeninen Cancer Research Institute, Vienna, Austria

Prof Heinz Ludwig speaks to ecancer about a randomised phase II study he presented at the virtual EHA 2020 meeting.

He explains that the trial is evaluating whether a carfilzomib-based regimen can overcome the negative impacts of high-risk cytogenetics in newly-diagnosed multiple myeloma (NDMM).

Prof Ludwig provides an update on the interim efficacy analysis of combined data of KRd (carfilzomib, lenalidomide, dexamethasone) versus KTd (carfilzomib, thalidomide, and dexamethasone) followed by maintenance with carfilzomib or control.

He also outlines the background, results and main conclusions of the study.

ecancer's filming has been kindly supported by Amgen through the ecancer Global Foundation. ecancer is editorially independent and there is no influence over content.

Actually we report on the outcome in patients, these are transplant non-eligible patients, treated with either carfilzomib Rev-dex or carfilzomib thalidomide dex. It’s a prospective randomised comparison. Patients received nine cycles and then they are randomised to one year carfilzomib maintenance versus control.

At this point in time, as the enrolment has not been completed, we report on patients which have been treated so far but they are combined, both arms are combined. The question is whether the treatment results in different outcomes in patients with high risk cytogenetics defined either by translocation [4;14] and/or deletion 17p, that is the usual high risk definition. We have another group which we call high risk plus/minus 1q21. So if you have either translocation [4;14] and/or deletion 17p and/or amplification of 1q21 you are considered high risk group number two. The question is whether there is a difference in response rate, progression free survival and overall survival at this point in time.

So the answer is quite straightforward. When we look at response rates actually the treatment is almost equally effective in patients with traditional high risk definition as well as in patients with high risk defined plus/minus 1q21 or standard risk. So the overall response rate varies between 90-100% with these three risk groups so there is no significant difference. When we look at patients with very good partial response or better or CR there is no significant difference between these three groups, standard risk, high risk or high risk group two.

We also looked at the MRD results but we checked MRD level only in patients with very good partial response or complete response. Actually we looked at 49 patients and 45% of those had MRD negativity. Bruno Paiva did the MRD testing so it’s high sensitivity, 10-6. So far patients with MRD positive have a shorter PFS as compared to MRD negative patients which is what is to be expected. Overall survival at this point in time doesn’t show any difference between the MRD positive and negative patients but with further follow-up probably it’s very likely that we’ll see a difference in these groups.

The other question which we raised was whether there is an impact of cytogenetic risk group on the outcome in terms of progression free survival. Interestingly, when we defined high risk [4;14] and/or deletion 17p actually patients did poorly with the carfilzomib based combinations, so they had a shorter progression free survival as compared to the standard risk patients. So the progression free survival was 24 months in the standard risk and 13.5 months in the high risk patients. But overall survival was similar. When we looked at the other high risk group with or without amplification of 1q21 actually there was no significant difference in progression free survival.

So at this point in time we can summarise and say we have very high response rates. Response rates are quite similar in the different risk groups. Progression free survival in patients with conventionally defined high risk cytogenetics but overall survival is at this point in time similar. When we looked at the other high risk group which includes the presence of 1q21, yes or no, plus the presence of [4;14] plus the presence or not of deletion 17p, so here the regimens were quite active, there was no difference in PFS.

In other words, the treatment is highly active in terms of response rate. In terms of progression free survival we have to… the median follow-up is, at this point in time, around 50 months. We have to look for longer follow-up in order to have more solid data and to see whether the difference in PFS in the high risk group still holds true with longer follow-up. But at this point in time overall survival is similar in both patient groups.

So it was relatively well tolerated, the combination – carfilzomib thal-dex, carfilzomib Rev-dex – but, as expected, there were some minor, or in a few patients significant, toxicities, particularly cardiac toxicity but overall the regimens were well tolerated.