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J.R. Jones et al.
nant in both the CR and non-CR series, stable progression was only seen in the non-CR series, (25%, 8 of 32, vs. 0%, 0 of 25; P=0.008) (Figure 5A). Breaking down the non-CR series further showed that stable progression was pre- dominantly associated with a PR (56%, 5 of 9 of PR; 13%, 3 of 23 of VGPR patients). No CR or nCR patients (0 of 24) had evidence of stable progression, with all patients showing branching or linear evolution (P=0.002) (Figure 5B). Consistent with a deep response being synonymous with a change in clonal architecture, 86% (6 of 7) of patients who achieved an MRD-negative state relapsed via a branching mechanism and 14% (1 of 7) via linear evolu- tion. The type of evolution leading to relapse had no impact on the time to relapse or overall survival (Online Supplementary Table S6).
Discussion
This study shows that an increase in mutational load, altered mutational profile, accumulation of deleterious structural lesions [particularly tMYC and gain(1q)], and a change in copy number profile are key molecular features of relapse. The depth of response to treatment has a sig- nificant impact on both the genetic landscape and the evo- lutionary patterns seen at relapse, with an increased muta- tional load being predominantly associated with the achievement of a CR. We also note that relapse from CR is associated with an altered mutational profile, with 63% (15 of 24) of the CR patients having evidence of loss or gain of known recurrently mutated genes in comparison to only 25% (8 of 32) of non-CR patients (P=0.006). This pattern was also seen for CNA and structural variants, with del(17p), tMYC, gain(1q), and loss of tumor suppres- sor gene regions, including CDKN2C, FAF1, FAM46C, RB1, and TRAF3, being seen more frequently in the patients relapsing after CR.
It has been shown that the progression through the mul- tistep transformation of MM is associated with an increased mutational load. This is well illustrated by stud- ies that have compared monoclonal gammopathy of undetermined significance, MM, and plasma cell leukemia. Our results are consistent with this observation, and we clearly show that an increased mutational load is an important factor in early disease progression following a good response to treatment.49,50 Similar findings are observed in other cancer types where a greater mutational load is associated with a more aggressive disease status, for example, lung cancer in smokers compared to non- smokers, and in malignant melanoma.51,52
A variety of subclonal patterns, including branching, lin- ear, and stable patterns, are seen at relapse (Figure 4A-D). The pattern of clonal change is most consistent with the hypothesis that branching evolutionary pathways are the predominant mechanism underlying relapse, especially if spatial variation is taken into account. Treatment can be seen as causing an evolutionary bottleneck, particularly in patients who achieve a deep treatment response, provid- ing a selective pressure for the emergence of pre-existent resistant clones. Importantly, these branching patterns and increased genetic damage in the clonal cells are hallmarks of effective treatment and achievement of deep responses. In contrast, the stable patterns seen in non-CR patients are most consistent with microenvironmental change, possi- bly as a consequence of the presence of treatment resistant
dominant clones at disease onset. This stable pattern is reminiscent of the results seen in the progression of smol- dering MM to MM, where the emergence of new muta- tions is infrequent, yet there is a profound change in clin- ical behavior.
Mechanistically, relapse in the setting of effective thera- py that results in the achievement of a CR is occurring either due to the emergence of low-level sub-clones that are undetectable at presentation, but which are selected for by treatment, or as a result of the acquisition of new mutations, albeit less likely given the short duration of remission. It may also be that the differences seen are the result of sampling bias, as previously shown by our group, although this is less likely given that all biopsies were obtained from the pelvis.53 The pattern of results seen with eradication of dominant clones and emergence of low-level clones with different pattern of mutation, and its association with CR, supports the concept that treatment can result in subclonal eradication. These findings high- light the therapeutic importance of achieving a CR to eradicate dominant clones present at the initiation of ther- apy. Supporting this as a therapeutic aim, we have recent- ly shown that high-risk patients achieving a molecular CR have very significantly improved 5-year survival rates.54
The results show that, even in MRD-negative CR, low- level resistant subclones remain, and therapeutic strategies need to be designed to address them. We believe this work supports the current best practice strategy of using different treatment regimens at successive relapses and shows why this approach is successful. We show that early relapse is either due to innate treatment resistance, requiring no change in the clonal structure, or due to a change of clonal architecture in response to effective ther- apy. Both mechanisms are consistent with a disease state at relapse that is resistant to the initial therapies used. This knowledge supports the use of combination regimens at relapse, incorporating agents with differing mechanisms of action to those used at presentation. This will be ana- lyzed in a planned comparator series of patients who achieve long-term remission in the trial. Our work here does, however, provide new insights into the mechanisms of early relapsing disease, revealing a different mechanism in those who achieve a deep therapeutic response and those who do not.
Interestingly, a recent study looking at non-small cell lung cancer has shown that mutational load may direct treatment choices, whereby the use of immunotherapy was associated with a longer and durable remission in patients with a greater mutational load at presentation.55 Therefore, as our understanding of myeloma biology increases, information such as mutational load may guide specific treatment modalities in the future. The use of lenalidomide maintenance is one of the first clinical strate- gies to address the residual cells that remain following ini- tial treatment. Using this approach, we did not see a signal of any adverse impact on the clonal cells as a result of this therapy. In particular, we did not see a signal for selection of mutations that could confer resistance to lenalidomide either at presentation or at relapse. Previous studies have suggested that such mutations may exist and could be rel- atively frequent in cell lines and heavily pre-treated patients, but in this study of newly diagnosed patients they were rare.56 However, we do describe a patient who received eight months of maintenance treatment, achiev- ing an MRD-negative CR who did relapse with a new
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haematologica | 2019; 104(7)