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they reach MRD negative status, implying that treatment resistance leading to incomplete clearance of clonal plasma cells represents the basis of early relapse and worse out- come. Previous studies analyzing the clonal evolution of myeloma during therapy have demonstrated different types of clonal changes, which are categorized as stable, lin- ear, and branching evolution of myeloma clones.5-7 Whereas clonally stable myeloma contains roughly the same muta- tional spectrum over the course of disease, linear evolution is characterized by gains of additional genetic aberrations on top of existing mutations, in contrast to a branching evo- lution, where clones with a sometimes completely new set of genetic aberrations appear over time. Still, the impact of the depth of remission on the clonal substructure, and the clonal behavior during relapse after maintenance therapy has not so far been studied in great detail. In this issue of the Journal, Jones et al. report their study in which they per- formed whole exome sequencing (WES) on diagnosis/relapse samples from a subset of 30 myeloma patients receiving lenalidomide maintenance and 26 patients without maintenance from a large myeloma treat- ment study (Myeloma XI trial), with a focus on patients with high-risk disease and early relapse.8,9 Strikingly, the authors observed a change in the mutational spectrum and an increase in the mutation load in the majority of relapse samples, whereas only a subset of patients showed a stable mutational landscape. Thus, patients achieving a good response to the initial therapy [either a very good partial remission (vgPR) or a complete response (CR)] seemed to go through a clonal bottleneck leading to a branched clonal evolution upon relapse, whereas most patients with incom- plete responses showed a linear evolution or stable clonal patterns (Figure 1). The authors did not identify specific mutations associated with relapse; for this type of analysis, higher patient numbers will be required. As has been described before, structural aberrations involving a gain of chromosome 1q or translocations targeting the Myc onco- gene on 8q were increased at relapse,10 with additional evi- dence of bi-allelic inactivation of common tumor suppres- sor genes like RB1, TRAF3, and TP53 in a subset of relapse patients.
Interestingly, maintenance therapy did not significantly impact the clonal composition predetermined by the response category. Similar to patients without mainte- nance, patients on lenalidomide therapy who achieved a CR presented with branching clonal architecture at relapse, whereas patients with a less profound response maintained more or less the clones already present at diagnosis. The finding that maintenance therapy did not seem to impact clonal patterns, while clearly having a clinical effect on dis- ease free survival,9 may hint at an immune-dependent, non- selective mode of action of lenamidomide, which leaves the clonal composition relatively unchanged. A more non-spe- cific, indirect mode of action of lenalidomide in these patients would also be supported by the observation that only a few mutations in the Cereblon/IRF4 pathway were detected in the relapsed patients under analysis. Alternatively (or additionally), maintenance therapy may not have had a sufficient effect on the overall clonal popu-
lation such as to create an evolutionary bottleneck. The study by Jones et al. centered on early relapse patients from the Myeloma XI trial who received 10 mg lenalidomide as maintenance therapy. Thus, the maintenance lenalidomide dose and the more aggressive biology of the myloma may have contributed to a reduced clonal selection pressure. Future studies will need to look further into the effects of maintenance lenalidomide on clonal evolution to confirm these findings, and to expand the analysis to patients with less aggressive disease. Reassuringly, lenalidomide mainte- nance therapy did not seem to increase the number of new genetic aberrations or the overall mutational load compared to the non-treated patients.
Overall, the study by Jones et al.8 demonstrates a clear connection between the depth of response and the pattern of clonal evolution in myeloma patients, with dormant new clones contributing to relapse in high-risk patients who ini- tially responded well to therapy. These findings raise the hope that further in-depth analysis of the clonal composi- tion of relapsed myeloma, including the application of novel techniques such as single cell sequencing,11 may shed light on the mechanisms of resistance leading to therapy failure, and help to guide subsequent salvage therapy. An in-depth analysis of the residual clonal substructure after intensive treatment may help to refine myeloma therapy in such a way as to ultimately prevent clonal escape, thus making an important contribution to the still elusive goal of achieving a cure for myloma patients.
References
1. McCarthy PL, Owzar K, Hofmeister CC, et al. Lenalidomide after stem-cell transplantation for multiple myeloma. N Engl J Med. 2012;366(19):1770-1781.
2. KunacheewaC,OrlowskiRZ.NewDrugsinMultipleMyeloma.Annu Rev Med. 2019;70:521-547.
3. Paiva B, Chandia M, Puig N, et al. The prognostic value of multipara- meter flow cytometry minimal residual disease assessment in relapsed multiple myeloma. Haematologica. 2015;100(2):e53-55.
4. Perrot A, Lauwers-Cances V, Corre J, et al. Minimal residual disease negativity using deep sequencing is a major prognostic factor in multi- ple myeloma. Blood. 2018;132(23):2456-2464.
5. Keats JJ, Chesi M, Egan JB, et al. Clonal competition with alternating dominance in multiple myeloma. Blood. 2012;120(5):1067-1076.
6. EganJB,ShiCX,TembeW,etal.Whole-genomesequencingofmulti- ple myeloma from diagnosis to plasma cell leukemia reveals genomic initiating events, evolution, and clonal tides. Blood. 2012;120(5):1060- 1066.
7. WalkerBA,WardellCP,MelchorL,etal.Intraclonalheterogeneityand distinct molecular mechanisms characterize the development of t(4;14) and t(11;14) myeloma. Blood. 2012;120(5):1077-1086.
8. Jones JR, Weinhold N, Ashby C, et al. Clonal evolution in myeloma: the impact of maintenance lenalidomide and depth of response on the genetics and sub-clonal structure of relapsed disease in uniformly treat- ed newly diagnosed patients. Haematologica. 2019;104(7):1440-1450.
9. Jackson GH, Davies FE, Pawlyn C, et al. Lenalidomide maintenance versus observation for patients with newly diagnosed multiple myelo- ma (Myeloma XI): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2019;20(1):57-73.
10. WalkerBA,WardellCP,BrioliA,etal.Translocationsat8q24juxtapose MYC with genes that harbor superenhancers resulting in overexpres- sion and poor prognosis in myeloma patients. Blood Cancer J. 2014;4:e191.
11. Ledergor G, Weiner A, Zada M, et al. Single cell dissection of plasma cell heterogeneity in symptomatic and asymptomatic myeloma. Nat Med. 2018;24(12):1867-1876.
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