clinical topic updates
Updates on Driver Mutations in Relapsed/Refractory Multiple Myeloma
Cytogenetic changes in multiple myeloma are among the most important prognostic factors, and treatments may have implications on the accumulation of these molecular alterations.
Professor and Chair
“In multiple myeloma, there are clones that appear and disappear during the course of treatment, and they may have different genetic abnormalities that can cause sensitivity or resistance to certain drugs.”
For me, a driver mutation is one that, when specifically targeted, will reverse the impact of the disease. A classic example of a driver mutation would be in chronic myeloid leukemia, where you get the translocation that creates the BCR-ABL protein that drives the disease. In that sense, I do not think that we have that clear-cut driver mutation in multiple myeloma.
We do, however, have genetic abnormalities in multiple myeloma that can impact outcomes, particularly high-risk genetic abnormalities such as 17p deletion (del[17p]), t(4;14), or t(14;16). All of these appear to have a negative impact on outcomes. And sometimes an alteration is actionable even though we do not have an agent available to target it. For instance, a patient with del(17p) likely needs more intensive maintenance therapy. While we do not have a specific drug to target 17p mutations or deletions, just knowing that these alterations are present tells me that the patient likely needs triplet maintenance.
One caveat may be the t(11;14) translocation, which, again, I am not sure that I would call it a true driver mutation, but it provides us with an understanding of the relevant biology. BCL-2 is not overexpressed in multiple myeloma, except in the t(11;14) subset, which appears to be enriched for sensitivity to BCL-2 inhibition. So, in that sense, t(11;14) does give us insight into a potential therapeutic strategy that may be considered for that specific subset of patients.
With respect to the issue of testing for these alterations, circulating tumor DNA is a promising technology that we are starting to explore, but I do not think that it is ready for prime time quite yet. A concern with circulating tumor DNA, as opposed to bone marrow testing, is the lack of certainty when an alteration is not detected. That is, you do not know whether it is absent because it is really gone or if it is due to other reasons (eg, the tumor clone has changed such that the alteration is no longer detected in the blood). In multiple myeloma, there are clones that appear and disappear during the course of treatment, and they may have different genetic abnormalities that can cause sensitivity or resistance to certain drugs.
Regarding the mutational burden from prior lines of therapy, it is true that you may see more mutations in the relapsed setting; however, this does not necessarily mean that the disease is more challenging to treat. In my experience, tumor mutation burden does go up with high-dose melphalan, but such therapy still results in a significant improvement in progression-free survival. Now contrast that with the use of low-dose alkylators such as oral cyclophosphamide (eg, bortezomib, cyclophosphamide, and dexamethasone [VCd]). When we look at VCd vs bortezomib, lenalidomide, and dexamethasone (VRd) for newly diagnosed multiple myeloma in the Multiple Myeloma Research Foundation CoMMpass study, we see significantly shorter progression-free survival in patients with greater-than-average somatic missense mutation load and predicted expressed neoantigen load.
As individuals with multiple myeloma are more heavily pretreated, there is a higher frequency of acquiring del(17p), mutations in TP53, or extra copies of chromosome 1q. These findings do appear to increase in heavily pretreated patients.
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Barwick BG, Gupta VA, Vertino PM, Boise LH. Cell of origin and genetic alterations in the pathogenesis of multiple myeloma. Front Immunol. 2019;10:1121. doi:10.3389/fimmu.2019.01121
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Miller A, Asmann Y, Cattaneo L, et al. High somatic mutation and neoantigen burden are correlated with decreased progression-free survival in multiple myeloma. Blood Cancer J. 2017;7(9):e612. doi:10.1038/bcj.2017.94
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