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Maintenance, response status, and subclonal structure at MM relapse
AB
*PR stable/non-stable vs. non-PR stable/non-stable (Fisher’s exact test)
Figure 5. The evolutionary patterns seen leading to relapse according to the depth of treatment response. (A) The evolutionary mechanism leading to relapse for the complete remission (CR) and non-CR series. Stable evolution was only seen in the non-CR patients (Fishers exact test, P=0.008). Branching evolution was the predominant mechanism leading to relapse in both CR and non-CR patients, with linear evolution also occurring, but in a smaller proportion of patients. (B) The evo- lutionary mechanism leading to response according to the depth of response. Over half (56%) of the patients who achieved a partial response (PR) as their best response prior to relapse progressed via a stable mechanism (P=0.002). A smaller proportion of very good partial response (VGPR) patients displayed stable pro- gression (13%). Branching evolution was dominant, and was seen in 75% of nCR patients and 67% of CR patients.
could not be linked to a change in the number of clones predicted by SciClone clustering, where a median number of seven clones was seen at relapse in both the CR and non-CR series (Figure 3). The same findings were noted for all 56 patients and when analyzed according to main- tenance strategy. No patient had evidence of the loss or gain of >2 mutational clusters at relapse, further suggest- ing that a change in the number of clones is not a major cause for change in the mutational load (Online Supplementary Table S5).
Lenalidomide maintenance has no impact on the mutational profile at relapse
There was no specific mutational, copy number or structural feature which characterized patients who received lenalidomide maintenance compared to observa- tion patients. Of patients who received lenalidomide maintenance, 83% (25 of 30) had a mutation in one or more of the recurrently mutated myeloma genes at some point during the disease course compared to 85% (22 of 26) of observation patients. Gain and/or loss of one or more mutation at relapse, including those in genes impli- cated in the mechanism of action of an immunomodulato- ry agent, were seen in 43% (13 of 30) of patients receiving lenalidomide maintenance and 35% (9 of 26) of the obser- vation patients (Figure 1B).
We did not identify a mutational signal consistent with the selection of clones carrying mutations associated with acquired resistance to lenalidomide. Five patients had mutations in DDB1 (n=2), SLC16A1 (n=2), and CRBN (n=1), but these were not confined to the cases of lenalido- mide maintenance, nor were they seen exclusively at relapse (Figure 1B). Mutations in other genes linked to the mechanism of action of lenalidomide, including regulator of cullins 1, cullin-4A, Ikaros, Aiolos, and Basigin, were not found at presentation or relapse in any patient.14,46-48 Mutations in MYC and IRF4, transcription factors known
to be down-regulated in response to immunomodulation, were seen in 2% (n=1) and 4% (n=2) of patients, respec- tively. However, consistent with an acquired mutation having a possible role in drug resistance, we identified one patient who had been exposed to eight months of lenalidomide maintenance and achieved flow cytometric minimal residual disease (MRD) negativity (minimum 5x105 cells interrogated) and who then went on to develop a novel CRBN mutation (p.Cys326Gly) at relapse; this is consistent with the emergence of resistance due to muta- tion at the immunomodulatory molecule binding site. The mutation was also present in a dominant clone, with a CCF of 0.71, further suggesting its presence may have impacted on the fitness of the tumor in relation to pres- sure from the immunomodulatory treatment (Online Supplementary Figure S6).
Branching evolution is the predominant process leading to relapse, particularly in patients achieving a deep treatment response
We observed three main evolutionary patterns at relapse: branching, linear, and stable. Branching evolution was characterized by both gain and loss of mutational clusters and was the predominant pattern, seen in 66% (37 of 56) of all cases (Figure 4A). Linear evolution character- ized only by the gain of mutations at relapse was seen in 20% (11 of 56) of cases (Figure 4B). The remaining 14% (8 of 56) had either the same mutational profile at both time points, and were classified as stable progression (n=7), or displayed a loss of a mutational cluster at relapse, classi- fied as stable progression with clone loss (n=1) (Figure 4C and D). There was no significant impact of induction or maintenance lenalidomide on the evolutionary pattern seen at relapse (Online Supplementary Figure S7).
We show that the depth of treatment response is the most important determinant of the evolutionary pattern seen at relapse. Although branching evolution was domi-
haematologica | 2019; 104(7)
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