Daratumumab-Based Regimen Shows Efficacy in All Patients With Multiple Myeloma, Regardless of Cytogenic Risk

In an interview with Pharmacy Times, Pieter Sonneveld, MD, PhD, a professor of hematology at the Erasmus University of Rotterdam, discussed findings from the PERSEUS study in multiple myeloma and how cytogenic risk analyses can play a role in treatment management. Importantly, Sonneveld said the benefits of the daratumumab-based regimen were seen in all patients, including those with high and standard cytogenic risk levels.

Q: Can you review what cytogenic risk means, particularly in the context of multiple myeloma?

Pieter Sonneveld, MD, PhD: Cytogenetic risk means that we look at diagnosis to the myeloma cells of the patients in the bone marrow, and if there are any changes in the chromosomes or DNA, yes or no, related to the disease. And these are not, let's say, errors or changes that are already present at birth. No, they occur in the abnormal, malignant myeloma cells. And there's a couple of those that have been identified as being high risk for the prognosis of those patients, especially abnormalities of chromosome, 14, 414, 1416, 1420. These are all technical terms for translocations between chromosomes, so they're partly exchanges between some chromosomes. And we don't always know what it means for the biology, but we know what it means for prognosis. And there are others as well, like the lesions of certain parts of a chromosome, and in the myeloma world we test these abnormalities and use them as prognostic factors to determine the outcome of treatment. And usually, patients with these abnormalities in their chromosome have worse outcomes, both in terms of response and in long-term outcomes, progressive free survival and overall survival. So, in the future, then you have more therapeutic options. We might use the detection of these abnormalities to choose a different regimen, maybe a more effective regimen for these high-risk patients. But until now, this has not been standard in clinical practice.

Q: How does cytogenetic risk determine treatment regimens and/or predict outcomes?

Sonneveld: So, right now, except in clinical trials where we test the concept of treating patients with these abnormalities more intensively or longer or both, but outside clinical trials, in routine clinical practice, this is not done. So, this is the next stage, I think, in myeloma treatment. Once we have, let's say, more effective therapeutic options, we might decide to treat patients without these abnormalities. So standard risk or good risk, if you want, with limited treatment, and treat the high-risk patients with extensive treatment. This is difficult because the chromosomal abnormalities that we can detect, the methods are rather crude, but they are improving. And also, we can detect comparable abnormalities during the course of the treatment. So maybe we can detect more precisely whether a patient is responding well, whether the malignant cells, the abnormal cells, disappear from the bone marrow. If they do, it's good. If they don't, we might consider changing to alternative treatments. So that's the concept that we have in mind, but it's not standardized.

Q: How is cytogenetic risk defined in the PERSEUS study?

Sonneveld: Yes, the risk in the PERSEUS study is defined as a couple of abnormalities: translocation 414, the translocations of 1416 and 1420, and deletion of part of chromosome 1770. You may be aware that recently, the definition of cytogenetic abnormalities has been revised. We call that the Barcelona criteria. It is not yet published, but we plan to. This will be a more extensive analysis of the abnormalities, and we plan to repeat that in the PERSEUS trial, as well, once these criteria have been published and accepted.

Q: What did the PERSEUS study find with regard to the benefits of D-VRd in patient subgroups based on cytogenetic risk?

Sonneveld: We see a benefit with daratumumab in all patient groups, including high risk and standard risk. So, in each of these groups, the daratumumab treatment, dara-VRd, significantly improves the response rate, the [complete response] rate, and progressive free survival. But what we do not see is that addition of daratumumab completely abrogates the high-risk definition of the patients. So, patients with high-risk disease, defined by cytogenetics, improve with daratumumab but not to the level of the standard risk patients. However, the gap between the 2 [groups] is much smaller than we have seen in other trials in the past.

Q: If you have one key takeaway, what would it be?

Sonneveld: We are observing improvement in treatment by adding novel drugs or novel antibodies created by biotechnology. This is a major step forward from traditional chemotherapy, and this is not the end. As I said, new treatments with bispecific antibodies with, let's say, cellular technology like CAR T cell is now being studied and will soon enter the clinic. And I think with those we may will make even more progress, and hopefully we will be able to achieve a cure in some patients.