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Maintenance, response status, and subclonal structure at MM relapse
sistent with an alteration in subclonal structure and a change in the nature of the dominant clone observed at relapse.
Gain(1q) was the most common new event at relapse, occurring in 13% (7 of 56) patients. Secondary transloca- tions to chromosome 8q, the site of MYC, also occurred more frequently at relapse, increasing from 21% (12 of 56) to 27% (15 of 56) (Online Supplementary Table S3).45 Consistent with translocations to MYC being late events, five patients had evidence of two separate MYC translo- cations at relapse. All patients with gain(1q) or tMYC at presentation had evidence of the lesion at relapse, illus- trating the driver status.
Bi-allelic inactivation of tumor suppressor genes located at sites of recurrent CNA are likely to be relevant media- tors of relapse. We show that bi-allelic inactivation events of RB1, TRAF3, and TP53 are important with 18% (10 of 56) of patients having evidence of bi-allelic inactivation of ≥1 gene at relapse, in comparison to 14% (8 of 56) at pres- entation. One patient harboring both a TP53 mutation and del(17p) at presentation lost evidence of the del(17p) at relapse, but maintained bi-allelic inactivation via expan- sion of a different subclone characterized by a TP53 muta- tion which had a higher CCF at relapse (0.55 vs. 0.83).
Table 2. Series characteristics.
Whole series (% of all)
N. of patients 56
Relapse following a complete response is characterized by a greater mutational load and a change in genetic profile
Patients achieving a CR had a significantly higher non- synonymous mutational load at relapse, with a median of 59 mutations compared to 40 at presentation (P<0.001). Non-CR patients had a similar mutational load at relapse, with a median of 39 mutations at both time points (P=0.63). Similar patterns were also seen in patients receiving or not receiving lenalidomide maintenance (Online Supplementary Table S4).
By comparing the profile of known recurrently mutated genes, we show that 67% (16 of 24) of CR cases had a change in mutational profile at relapse compared to only 25% (8 of 32) of non-CR cases (P=0.003) (Figure 2A); these findings were a feature of both the observation and lenalidomide maintenance series (Figure 2B and C). Consistent with the mutation profile changes described, gain and loss of the structural lesions del(1p), del(13), del(14), del(17p), gain (1q), and tMYC at relapse was more common in the CR series, with 42% (10 of 24) of patients having a change in the profile of these aberrations com- pared to 28% (9 of 32) of non-CR patients (Online Supplementary Figure 5S). The changes in mutational load
Maintenance randomization
Lenalidomide (% of group)
30
Observation (% of group)
26
Medianage 68 67 69 Gender
Male
Female
Pathway
TE
TNE Induction
Thalidomide
Lenalidomide
Best response
CR series (CR/nCR)
Non-CR series (VGPR/PR)
Median maintenance duration (months, range) Median number of maintenance cycles (range) Median PFS (months, range)
Presentation ISS
I
II
III Missing
Cytogenetic risk*
High risk
Ultra-high risk
28 (50) 28 (50)
22 (39)
34 (61)
29 (52) 27 (48)
24 (43)
32 (57) 10 (1-27) n/a
19 (8-51)
13 (23) 21 (38) 21 (38) 1 (2)
20 (36)
7 (13)
13 (43) 17 (57)
11 (37)
19 (63)
15 (52) 15 (56)
14 (47)
16 (53) 10 (1-27) 7 (1-28) 19 (8-51)
5 (17) 12 (40) 12 (40) 1 (3)
12 (40)
5 (13)
15 (58) 11 (42)
11 (42)
15 (58)
14 (48) 12 (44)
10 (38)
16 (62) 9 (1-22) n/a
19 (8-34)
8 (31) 9 (35) 9 (35)
8 (31)
2 (8)
*High risk defined as one of t(4;14), t(14;16), t(14;20), gain(1q), and del(17p). Ultra-high risk defined as two lesions.TE: transplant eligible; TNE: transplant ineligible; CR: com- plete response; nCR: near CR;VGPR: very good partial response; PR: partial response; PFS: progression-free survival; ISS: International Staging System; n/a: not applicable.
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