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Letters to the Editor
Chromosome 1q21 abnormalities refine outcome prediction in patients with multiple myeloma – a meta-analysis of 2,596 trial patients
The prognostic value of additional copies of chromo- some 1q remains debated. To address this uncertainty, we performed a validation and meta-analysis of gain(1q) (3 copies) and amp(1q) (≥4 copies) in 2,596 patients with newly diagnosed multiple myeloma (NDMM) from three phase III trials. Gain(1q) and amp(1q) were both associat- ed with shorter progression-free survival (hazard ratio [HR]=1.50, 95% confidence interval [95% CI]: 1.16-1.95, P=0.002 and HR=1.65, 95% CI: 1.25-2.19, P=4.8x10-4, respectively) and overall survival (HR=1.85, 95% CI: 1.43-2.39, P=2.6x10-6 and HR=2.28, 95% CI: 1.42-3.64, P=5.8x10-4) by meta-analysis as well as in each trial indi- vidually; there was no statistically significant difference in outcome between the two copy number states. Gain(1q)/amp(1q) was independently prognostic in the context of the Revised International Staging System (R-ISS) and refined risk prediction by enabling identifica- tion of ultra high-risk tumors across trials.
Additional copies of 1q21 are one of the commonest genetic abnormalities in multiple myeloma;1 however their value as a prognostic marker remains controversial. While several studies showed that 1q21 gain is an inde- pendent poor prognostic factor, other studies have failed to support a relationship.2-7 Previous studies have often been small or conducted outside of clinical trials, thus having limited power to demonstrate a relationship, especially as assays can be complicated by heterogeneity in terms of copy number, i.e., gain versus amp(1q).6 In contrast to t(4;14) or del(17p), 1q21 status is not included among the high-risk markers listed by the International Myeloma Working Group’s R-ISS,8 and as a result it has invariably not been reported in most clinical trials over the past decade. Its prognostic relevance in the context of modern therapies is hence poorly defined.
To examine the relationship between gain(1q) and amp(1q) and prognosis and to address shortcomings in earlier studies we investigated 2,596 NDMM trial patients receiving controlled therapy with a proteasome inhibitor or an immunomodulatory drug.
We included patients from three independent phase III trials of NDMM with comparable baseline characteristics
Table 1. Clinical and laboratory characteristics in relation to 1q status in the GMMG and Myeloma XI trials.
Variable N.
Male gender 512 Age 880 WHO PS 873
0 1 2 3+
Hemoglobin (g/L) 865 Platelets (x109/L) 880
(mmol/L)
Creatinine 867
(mmol/L)
Calcium 878 (mmol/L)
ISS 857
I II II
LDH > ULN 860 t(4;14) 876 t(14;16) 860 del(17p) 879 R-ISS 819
I II III
Light chain l 879
GMMG HD4 and MM5 combined
1q21 normal Gain(1q21) Amp(1q21) n=556a n=244a n=80a
P-valueb
0.4 0.09
<0.001 <0.001 0.03 0.12 0.006
0.014 <0.001 0.009 0.9 <0.001
<0.001
NCRI Myeloma XI
N. 1q21 normal Gain(1q21) Amp(1q21) n=1139a n=460a n=117a
P-valueb
0.1 0.5
<0.001 <0.001 0.018 <0.001 0.006
0.8 <0.001 0.031 0.6 0.004
<0.001
320 (58%) 58 (52, 63)
237 (43%) 269 (49%) 41 (7.4%) 5 (0.9%) 110
(95, 123) 254 (203, 312) 92 (76, 121) 2.32 (2.20, 2.48)
229 (42%) 186 (34%) 127 (23%) 100 (18%) 37 (6.7%) 7 (1.3%) 65 (12%)
151 (29%) 312 (60%) 56 (11%)
147 (26%)
144 (59%) 58 (52, 64)
106 (44%) 105 (44%) 21 (8.7%) 9 (3.7%) 99
(88, 114) 224 (170, 282) 98 (80, 129) 2.36 (2.20, 2.50)
79 (33%) 86 (36%) 75 (31%) 66 (28%) 38 (16%) 10 (4.3%) 27 (11%)
53 (23%) 132 (58%) 43 (19%)
98 (40%)
48 (60%) 58 (53, 64)
31 (39%) 39 (49%) 7 (8.8%) 3 (3.8%) 97
(88, 113) 186 (144, 262) 105 (83, 141) 2.39 (2.25, 2.51)
23 (30%) 22 (30%) 30 (41%) 19 (24%) 29 (37%) 4 (5.1%) 8 (10%)
15 (21%) 36 (50%) 21 (29%)
38 (48%)
1034 691 (61%) 1716 67 (59, 72) 1644
406 (37%) 471 (43%) 165 (15%) 56 (5.1%)
1716 108 (95, 120)
1716 241 (194, 300)
1716 86 (71, 109)
1715 2.41 (2.31, 2.52)
1032
1427 289 (30%) 1716 90 (7.9%) 1716 25 (2.2%) 1716 101 (8.9%)
868
1701 320 (28%)
274 (60%) 67 (60, 74)
146 (33%) 192 (44%) 67 (15%) 31 (7.1%) 105 (93, 117) 222 (172, 275) 90 (72, 115) 2.41 (2.33, 2.57)
59 (21%) 127 (46%) 90 (33%) 117 (31%) 74 (16%) 21 (4.6%) 35 (7.6%)
25 (11%) 163 (71%) 40 (18%) 179 (39%)
69 (59%) 66 (62, 72)
42 (38%) 40 (36%) 20 (18%) 8 (7.3%) 98
(89, 109) 198 (138, 250) 93 (79, 118) 2.45 (2.38, 2.63)
10 (14%) 26 (37%) 35 (49%) 32 (33%) 37 (32%) 4 (3.4%) 12 (10%)
4 (6.9%) 36 (62%) 18 (31%) 50 (43%)
183 (27%) 298 (44%) 204 (30%)
aStatistics presented as n (%) or median (interquartile range). bStatistical tests performed: χ2 test of independence; Kruskal-Wallis test; Fisher exact test GMMG: German- speaking Myeloma Multicenter Group;NCRI:National Cancer Research Institute;WHO PS:World Health Organization performance status; ISS.International Staging System; LDH: lactate dehydrogenase; ULN: upper limit of normal; R-ISS: Revised International Staging System.
96 (16%) 401 (69%) 85 (15%)
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