Evaluation of MRD negativity in patients with relapsed or refractory multiple myeloma treated in the CANDOR study

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Published: 7 Dec 2020
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Prof Ola Landgren - Memorial Sloan Kettering Cancer Center, New York City, USA

Dr Landgren speaks to ecancer about the study presented at ASH 2020 regarding the evaluation of minimal residual disease (MRD) negativity in patients with relapsed or refractory multiple myeloma treated in the CANDOR study.

He says CANDOR is a multicentre, phase 3, randomised study of adult patients with relapsed or refractory multiple myeloma (RRMM) previously treated with 1-3 prior lines of therapy. He moves on to explain the methodology of the study and says that 466 patients received carfilzomib, dexamethasone, and daratumumab (KdD) or carfilzomib and dexamethasone (Kd) in 2:1 randomisation.

Dr Landgren explains that the primary endpoint, KdD demonstrated superior progression-free survival (PFS) vs Kd. He further mentions some of the key results of this study and the future impact these results can have on the treatment of multiple myeloma patients.

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.

The CANDOR study is a new randomised phase III trial focusing on patients with relapsed or refractory multiple myeloma who previously have received one to three prior lines. The main analysis focuses on progression free survival; it was just published some weeks ago in the Lancet. The study shows that the experimental arm that consists of carfilzomib, daratumumab, and dexamethasone has a superior progression-free survival compared to the control arm, which is carfilzomib and dexamethasone. And that has also led to an FDA approval.

What was the method and purpose of evaluating MRD negativity in these patients?

At this current presentation at ASH 2020, I am about to present additional information beyond the Lancet publication. The Lancet publication focuses on the primary endpoint of progression-free survival, but this abstract focuses on one of the pre-specified secondary objectives, which is MRD detection. Specifically, we conducted VDJ sequencing of samples from patients treated on this clinical trial. We were interested to see what is the MRD rate at a pre-specified time point in patients treated with carfilzomib, daratumumab, dexamethasone versus carfilzomib and dexamethasone. We also did additional sub-analysis as part of the protocol around MRD: we looked at the best MRD negativity response, we looked at MRD independent of what the serum markers showed, and we also conducted a sub-analysis where we looked at deeper degrees of MRD negativity than what typically is used, 10-4 – we went down to 10-6.

Can you explain the key results?

The key result of this presentation is that the three-drug combination with carfilzomib, daratumumab and dexamethasone has a significantly higher rate of MRD negativity compared to the control arm of carfilzomib and dexamethasone. Looking at the pre-specified time point, which is twelve months after the enrolment on the study, there are patients who are in a complete response. The MRD rate is 12.5% versus 1.3% respectively for the KRd versus Kd arm. Looking at additional measures of MRD, when we look at the best overall MRD negativity rate at any time, we see that this three-drug combination with carfilzomib, daratumumab, dexamethasone goes as high as 22.8% versus 5.8% of the control arm. The reason that we see that these numbers keep on going up I do think reflective of what we have seen in many other studies. We see that the depth continues to deepen over time. We also do see that patients can reach MRD negativity in some cases while there still could be a low level of serum immunoglobulin present in the blood from the disease. I think this is because we can effectively kill the myeloma cells and achieve MRD negativity in the marrow while the clearance of the monoclonal protein may take a little bit longer. This is something that we have now started to see in different scenarios with effective combination therapies, and also we see these for example with CAR T-cell therapies where we effectively can eradicate cells, but the proteins are lingering for an extended period of time. So I think there will be future publications on this data, future presentations showing higher and higher rates of MRD negative. That would be my projection.

How can this study impact the treatment of relapsed multiple myeloma in the future?

These results build on the Lancet publication that just came out showing that carfilzomib daratumumab dexamethasone has a superior progression free survival compared to carfilzomib dexamethasone. They expand on that in the manner that they provide detailed data supporting that you can achieve very deep responses with the three-drug combination. In the best overall MRD negativity rate at any time, almost a quarter of the patients have achieved MRD negativity. As I already pointed out, I think it’s likely that these results will continue to improve over time, because it’s highly tolerable and it’s highly effective therapy, so if patients keep on staying on this regimen going forward I would project that we will see deeper and deeper responses in more and more patients, I think the results are going to be even more strikingly superior for the three-drug combination

Is there anything else you’d like to add?

In addition to the primary endpoint of this presentation and in addition to the additional perspectives of looking at MRD at any time, we also conducted a sub-analysis when we looked at 10-5 or one cell in 100,000, and 10-6, one cell in a million, so looking at deeper and deeper degrees of MRD negativity. What we show is that in the setting of three drugs, we pick up some patients actually being MRD negative 10-6. That’s about one in five of the patients that are in this category of no detectable disease. In the two-drug combination, we did not see any of the patients going this deep. So I think the three-drug combination is highly effective from the primary endpoint of the trial, PFS, it’s highly effective when we set the bar at 10-5 for MRD negativity, which is the established cut-off for talking about MRD negativity, but it also shows that one in five patients that are heading into this MRD negativity space goes very very deep. So I think again it supports what I have said multiple times: I think this is a highly effective therapy, and I think the results will keep on becoming stronger and stronger as we follow patients going forward.