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Exploring Results of the IsKia Trial in Newly Diagnosed Multiple Myeloma With Annemiek Broijl, MD, PhD

In this interview from the 2023 American Society of Hematology (ASH) Annual Meeting, Dr. Annemiek Broijl, Hematologist at Erasmus MC Cancer Institute in the Netherlands, discusses the IsKia trial, of which she is the Co-Primary Investigator, and its unique primary end point of measurable residual disease (MRD).  

Oncology Data Advisor: Welcome to Oncology Data Advisor. I'm Keira Smith. Today, we're here live at the ASH Annual Meeting, and I'm joined by Dr. Annemiek Broijl. Thanks so much for coming on the show today.

Annemiek Broijl, MD, PhD: Thank you so much for being here.

Oncology Data Advisor: To start off, would you like to introduce yourself and share what your work focuses on?

Dr. Broijl: My name is Annemiek Broijl. I work as a Hematologist in Rotterdam, the Netherlands. I'm part of the European Medical Network (EMN) and President of the Young EMN. Together with Francesca Gay, I'm a Principal Investigator of the study that was presented today, the IsKia study or the EMN24 study, as we call it in Europe.

Oncology Data Advisor: I'm looking forward to hearing about the results of the IsKia trial, which is of isa-KRd (isatuximab/carfilzomib/lenalidomide/dexamethasone) for newly diagnosed multiple myeloma. For background, would you like to tell us a little bit about what the current standard treatment is for transplant-eligible newly diagnosed multiple myeloma, as well as what the IsKia trial investigated in this setting?

Dr. Broijl: What we do now as a standard therapy is we give a quadruplet regimen, which is based on the CASSIOPEIA study, a study that was also conducted in Europe. That study compared dara-VTd (daratumumab/bortezomib/thalidomide/dexamethasone) versus VTd alone. That led to the European Medical Agency (EMA) approval of dara-VTd, which is actually the current standard.

Then you may ask, "Oh, then why is KRd the standard in this new trial?" Well, that is based on the efficacy of KRd that we know and that we have found already in the FORTE trial, for example. Also, other trials like the CONCEPT trial have looked at Isa-KRd in high-risk patients. We were looking at the efficacy of isatuximab combined with KRd in induction and in consolidation—after high-dose melphalan and transplantation, but also with the addition of a light maintenance phase of isatuximab, carfilzomib, lenalidomide, and dexamethasone—with carfilzomib, lenalidomide, and dexamethasone in a lower frequency and/or a lower dose. The addition of isatuximab was the experimental arm, and we compared it to the same as what I just said, but then only KRd.

Oncology Data Advisor: Great. What was the study investigating, and what was the primary end point?

Dr. Broijl: The primary end point was quite a novel end point, MRD. As you know, a lot of studies still use progression-free survival (PFS). Actually, the key secondary end point in our study is PFS because that is still the main end point that is also approved by the EMA and by the FDA to have studies registered. However, we know that with the longer PFS to follow, MRD is another endpoint that is very attractive to use. We used MRD with next-generation sequencing (NGS) at 10-5 and also 10-6, but 10-5 was the primary end point post-consolidation.

Oncology Data Advisor: Is this unique that MRD was the primary end point as opposed to survival?

Dr. Broijl It is actually quite unique. Many studies use it now as a co-primary end point, and there are studies that are now using it as a primary end point. Hopefully, we are moving towards using MRD as a future accepted end point by the EMA and FDA. It is quite new, but we are thinking about the future already.

Oncology Data Advisor: What were the results of the trial, and did it meet the primary end point?

Dr. Broijl: Yes, it did meet its primary end point. We saw post-consolidation with NGS with a sensitivity of 10-5 that patients receiving isa-KRd got to an MRD negativity rate of 77% versus 67% in the KRd arm. This was statistically significant with an odds ratio of 1.67.

Oncology Data Advisor: That's great. What were some of the other interesting or striking findings in the trial?

Dr. Broijl: We saw that we have another opportunity to measure with a sensitivity of 10-6 NGS. Then we saw even a higher difference between isa-KRd and the KRd arm, with isa-KRd showing an MRD negativity rate of 67% versus 48%. This actually shows that MRD with 10-6 could even be a stronger predictor for progression-free survival outcomes, because that shows a bigger difference between the isa-KRd and KRd arms.

The most striking result was actually the effects that isa-KRd had in all risk groups. We looked at the risk groups in different ways. We looked at patients who had one high-risk cytogenetic abnormality, and we looked at patients who have two or more high-risk cytogenetic abnormalities, which include known cytogenetic abnormalities like deletion 7p and translocation 14;16. We also added 1q gain or 1q amplification to that. We saw that patients with one high-risk cytogenetic abnormality actually have the same MRD negativity as the patients who are standard-risk. That is actually quite a striking finding.

Even when you look at the patients with two or more high-risk abnormalities—and we know that they always do worse, even if you give quadruplet therapy—the numbers are small, but the NGS level at the 10-6 rate was the same. It was 77% versus 79% in the standard versus very high–risk groups. That was really striking that even if patients are really high-risk, they do perfectly well on Isa-KRd. However, if you compare that to KRd, then you do see a decrease in the rate of MRD negativity when you go from standard-risk to high-risk to very high-risk. That shows the strength of isatuximab combined with KRd and makes it very clear.

Oncology Data Advisor: Those are very powerful results. To put it into context a little bit, how do these results compare with other treatments for multiple myeloma, and what do they mean for the future treatment of multiple myeloma?

Dr. Broijl: I think that it's still too early to say, because we are looking at MRD data. We do know that MRD correlates with PFS. We also do see that all the quadruplet therapies give high MRD rates, and those are quite comparable, but we do not have PFS data yet. As they always say, comparing across trials, we do that, but it's actually not advisable to do. I think that there could be a place, but we need to have a way to sustain the MRD data and even the PFS data too. I think that the sustained MRD data will say more, and we hope to have that data maybe a year from now. But for now, it's too difficult to say how that compares to the other very nice results from other studies.

Oncology Data Advisor: That makes sense. What are some of the other next steps for the trial and for this regimen?

Dr. Broijl: The next step is to have longer follow-up data to look at sustained MRD and to hopefully also have future PFS data. Of course, we'll have that, but we just have to wait for it. I think that the sustained MRD data is something that will show more about what kind of position in which we can see Isa-KRd in the future.

Oncology Data Advisor: Wonderful. Anything else you'd like to mention about this trial and its significance?

Dr. Broijl: Something that I would like to mention is the safety, because we are always a little bit afraid of carfilzomib and cardiac problems. Of course, we are looking at a quite young population of patients who are transplant-eligible, but still, there's always the concern about what happens with cardiac or thromboembolic effects. Actually, these were quite minimal. It was not something that was really obvious. If we look at the data, grades 3 to 4 were less than 1% in both groups, isa-KRd and KRd, and it was less than 5% for grades 0 to 4. Also, thromboembolic events are very low, around 6% to 11%, with hardly any grade 3 to 4 problems. Neuropathy is always the thing that is a problem with proteasome inhibitor–containing regimens, such as bortezomib/lenalidomide/thalidomide. This is a problem we hardly see with the combination of KRd or Isa-KRd, and it is even 0% for grades 3 to 4 and only between 12% to 30% for grades 1 to 2 for both Isa-KRd and KRd.

Oncology Data Advisor: That's very impressive, and I'm sure going forward, that will be such a comfort when using the regimen.

Dr. Broijl: It certainly is. And the trial was really well-received by the whole community in the plenary session, and there were so many people there, so that was really nice to see.

Oncology Data Advisor: Definitely. Well, it's wonderful to hear about the trial, and this is really such a great picture you painted of the efficacy and the MRD results, as well as the safety. Thank you for providing such a clear picture of all the sides of it.

Dr. Broijl: Thank you so much.

About Dr. Broijl

Annemiek Broijl, MD, PhD, is a Hematologist at the Erasmus MC Cancer Institute in Rotterdam, the Netherlands. She serves as Chair of the Young European Myeloma Network (EMN) and is actively involved with the International Myeloma Working Group (IMWG). At Erasmus, she combines patient care with translational studies in the Myeloma Research Lab, with particular focus on molecular characterization of plasma cells, the bone marrow microenvironment, the adaptive immune system, and identification of factors associated with resistance and sensitivity to therapy.

For More Information

Gay F, Roeloffzen W, Dimopoulous MA, et al (2023). Results of the phase III randomized IsKia trial: isatuximab-carfilzomib-lenalidomide-dexamethasone vs carfilzomib-lenalidomide-dexamethasone as pre-transplant induction and post-transplant consolidation in newly diagnosed multiple myeloma patients. Presented at: 2023 American Society of Hematology Annual Meeting. Abstract 4. Available at: https://ash.confex.com/ash/2023/webprogram/Paper177546.html

Transcript edited for clarity. Any views expressed above are the speaker's own and do not necessarily reflect those of Oncology Data Advisor. 


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