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Maintenance, response status, and subclonal structure at MM relapse
CRBN mutation. It is likely that the mutation occurred by chance, but that, in true Darwinian fashion, in the pres- ence of lenalidomide, it conferred a survival advantage to the malignant cells harboring it. Recent analyses indicating that prolonged exposure to lenalidomide is not linked to an increased incidence of second primary hematologic malignancies when used in combinations excluding oral melphalan may be supported by a lack of evidence of mutagenesis leading to treatment resistance in this work, although it is acknowledged that larger analyses using patients with prolonged remissions are required.24,57 It is important to note that the patients studied here relapsed early and that they were selected because of this charac- teristic, as it had previously been suggested that exposure to lenalidomide could enhance progression of such cases post maintenance. However, we did not find any evidence to support such a hypothesis.
It does remain important to evaluate the impact of maintenance on low-risk cases who are long-term sur- vivors, a question not addressed in this study. In addition, we acknowledge that clonal structure may be further assessed using single cell analysis. However, for the moment, the challenges of obtaining individual malignant plasma cells from large series of patients at multiple dis- ease time points has proved to be a significant barrier. In this series of patients, however, we do see evidence of par- allel evolution, as previously described using single cell technology, further validating the clonal changes described here.23 An example is seen in a patient with bi-
allelic inactivation of TP53 at presentation characterized by del(17p) and TP53 mutation, but only the presence of a TP53 mutation at relapse. In this case the clone with del(17p) was no longer detectable at relapse, suggesting it was treatment sensitive and/or out-completed by a more aggressive treatment insensitive clone harboring a TP53 mutation that had expanded following treatment, con- firmed by a higher CCF at relapse (0.55 vs. 0.83).
In this group of high-risk early-relapsing patients, we show that relapse is a result of the dynamic interplay of evolutionary processes based on the capacity of clonal cells to adapt to their bone marrow microenvironment as a result of new mutations, copy number change, and the selective pressure of the treatment used. Specifically, the depth of response is a critical feature that impacts the evo- lutionary patterns seen at relapse, rather than the use of lenalidomide maintenance.
Acknowledgments
We are thankful to all the patients who have taken part in the Myeloma XI trial, from which samples used in this analysis were obtained. We thank the Data Monitoring and Ethics Committee (DMEC) and Trial Steering Group Committee (TSG) for their support and guidance throughout the trial.
Funding
Myeloma XI was funded by Cancer Research UK and received unrestricted educational grants from Celgene, Takeda and Merck.
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