Table 3 del(17p) biallelic vs. haploinsufficiency and cancer clone fraction (CCF).
From: High-risk disease in newly diagnosed multiple myeloma: beyond the R-ISS and IMWG definitions
Reference and setting | Number of patients with del(17p) | Incidence del(17p)/TP53 mutation | CCF cutoff for del(17p) detection | % double hita among del(17p) | Impact of biallelic/double hita vs. monoallelic inactivationb | CCF impact on outcomes |
|---|---|---|---|---|---|---|
Corre et al. [7]; NDMM treated with intensive strategy in France | 121 | NA | >55% | 37.2% | TP53 biallelic inactivation vs. del(17p) alone: median OS 36.0 vs. 52.8 months (P = 0.004) del(17p) monoallelic v control (n = 2505): OS 52.8 vs. 152.2 monthsc | CCF >55% choosen based on Thakurta et al. [79] data that showed virtually all patients with TP53 biallelic inactivation display the deletion in more than 55% of plasma cells |
Thakurta et al. [79]; MGP | 108d | NA | NA | 25.9% | Double-hit PFS (P<0.01) and OS (P<0.01) worse compared to haploinsufficiency | CCF <55% vs. >55%: • OS: 36 vs. 84.1 months • PFS: 14.3 vs. 23.9 months |
97d | 9%e | NA | 3.7% | On MV analyses: • PFS: only biallelic TP53 interactions significant • OS: only biallelic TP53 interactions significant | The CCF of the 63 driver genes higher in oncogenes than tumor suppressor genes (P = 0.001). TP53 was the notable exception, with a high CCF | |
D'Agostino et al. [19]; CoMMpass study (NCT01454297) | 111 | 13% | 20% | 24% | Early PDf • del(17p): 17.1% • TP53 mutation: 50%, • Biallelic: 41.4% MV analysis: TP53 mutation OR 3.78 (P < 0.01) predicts PD within 24 months | CCF >50% vs. 20% predictive of early progression or death within 24 months: 25% vs. 17.1% |
Thanendrarajan et al. [80]; total 3–5 trials | 76 | 10% | 20% | 9.2% | Homozygous del17p or both del17p and TP53 mutation as compared to halploinsufficiency • 3-year OS: 84% vs. 29% (P = 0.02) • 3-year PFS: 73% vs. 29% (P = 0.04) | CCF >60% optimalg • HR for PFS: 1.53 (P = 0.03) • HR for OS: 1.69 (P = 0.013) CCF based on GEP70 score: • GEP70 low risk: no cutoff predictive • GEP70 high risk: CCF >60% predictive ◦ 3-year OS 73 vs. 87%; P = 0.002 ◦ 3-year PFS 64 vs. 81%; P = 0.004 |
Shah et al. [40]; UK NCRI Myeloma IX and XI trials | 192 | 10.8% | 10–20% | 2.4% | hMV analyses OS Myeloma XI trial: biallelic v monoallelic deletion/loss of TP53: • Heterozygous TP53 deletion/loss: HR 2.13 (1.58–2.86)/HR 2.18 (1.35–3.52) • Homozygous TP53 deletion/loss: HR 2.98 (1.22–7.26)/HR 4.31 (2.03–9.18) | iThree groups associated with OS: • CCF 10–20%: HR of 1.8 (P = 0.01) • CCF >50%: HR of 2.9 (P = 5.6 X 10–7) • CCF 95–100%: HR of 2.2 (P = 0.0002) |
Avet Loiseaeu et al. [81]: IFM99 | 58 del(17p) patients | 11% | 10% | NA | NA | CCF of 60% for del(17p): event-free survival 14.6 vs. 34.7 months |
Merz et al. [82]; single center Germany | 110 del(17p) patients | NA | 10% | NA | NA | CCF cutoff >60% vs. 10–60%: • PFS: 19 vs. 26 months, P = 0.03 • OS: 30 vs. 54 months, P = 0.09 |
An et al. [70]; single center China | 22 del(17p) patients | 6.6% | 20% | NA | NA | MV analyses: CCF>50% • PFS: HR, 2.455; P<0.001 • OS: HR, 1.754; P<0.001 |
Cohen et al. [83]; multi-institution (n = 8) | 60 del(17p) patients | NA | 5% | NA | NA | CCF cutoff >50%: • PFS: HR 1.7; P = 0.08 • OS: no CCF predictive |
Lakshman et al.; single institution [84] | 310 | NA | 7% | NA | NA | Median CCF of the entire cohort: 69.5% • PFS: 40% (P = 0.014) and 50% (P=0.027) CCF predicted PFS • OS: cutoff values from 20 to 60% did not predict OS |
