ASH 2021 | The immune microenvironment predicts sustained MRD-negativity after D-KRd treatment for myeloma
Furthering our understanding of the mechanisms of disease resistance is an important focus in multiple myeloma research in order to tackle treatment failure. Gareth Morgan, MD, PhD, FRCP, FRCPath, Perlmutter Cancer Center, NYU Langone Health, New York, NY, outlines the details of an investigation looking at factors able to predict sustained measurable residual disease (MRD)-negativity in patients with newly diagnosed myeloma treated with daratumumab, carfilzomib, lenalidomide, and dexamethasone (D-KRd). Whole genome sequencing of malignant plasma cells and single cell RNA-sequencing of the bone marrow cellular content was conducted. After 29 months of follow-up, 51% of patients had sustained MRD for more than a year after treatment completion. Several genomic events were found to be associated with MRD-positivity and conversion, including del XBP1, del 13, and IKFZ3. Features of the bone marrow microenvironment were also impactful, and its composition was shown to correlate with the tumor genomic architecture. Additionally, significant changes in the microenvironment were seen between paired samples at baseline and the end of induction. This interview took place at the 63rd ASH Annual Meeting and Exposition congress in Atlanta, GA.
Transcript (edited for clarity)
What we have is that we are collaborating with our collaborators who are now in Miami, who’ve treated people with a four-drug regimen in the upfront setting. And those who’ve given unprecedented response rates. So this is KRd-DARA and Dex, or DARA-KRd, which however you want to call it. But the question is, are there risks factors in that group that predict outcome? And so we took a group of patients that have been treated in that fashion, 10 of which got a complete response and sustained MRD and 10 who were poor responders, did single cell analysis and then looked at the microenvironment in those patients...
What we have is that we are collaborating with our collaborators who are now in Miami, who’ve treated people with a four-drug regimen in the upfront setting. And those who’ve given unprecedented response rates. So this is KRd-DARA and Dex, or DARA-KRd, which however you want to call it. But the question is, are there risks factors in that group that predict outcome? And so we took a group of patients that have been treated in that fashion, 10 of which got a complete response and sustained MRD and 10 who were poor responders, did single cell analysis and then looked at the microenvironment in those patients. And we find that they have differences in their monocyte populations, and differences in their B-cell population. So we think, and we’ll present that data to say those two different cellular populations are really governing the response of these immunotherapy targeted regimens like KRd-DARA.
But in addition, we did a lot of whole genome sequencing as well, and we show that certain subtypes, such as, gain of 22, loss of 21, at specific loci, are really important in governing the outcome as well. So in this kind of small targeted study, we think we found new prognostic factors for targeted immunotherapy that we can now go out, and ask in other trials, whether these are true prognostic factors that we can use in the clinic. So again, it’s a really interesting focused study to give you insights that you can then take to large clinical trials and validate them. So it’s going to change patient management, I think in the future, where we’ll really be able to tell good responders, bad responders, and personalize the therapies they use.
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