. 2022 May 30;12(5):83. doi: 10.1038/s41408-022-00679-5

Table 4.

Whole-genome/-exome sequencing.

	Number of patients	Source of patients	Genomic findings of note	High-risk factors identified
Myeloma genome Project [6, 17]	1273	• Myeloma XI trial, • Dana-Faber Cancer Institute/Intergroupe Francophone du Myelome • Multiple Myeloma Research Foundation CoMMpass study	• 63 driver genes identified including novel oncogenes PTPN11 (activator of MEK/ERK signaling), PRKD2 (protein kinase D), IDH1, and IDH2 (DNA methylation), and SF3B1 (spliceosome factor) • Identified novel tumor suppressor genes including UBR5 (a ubiquitin ligase) and HUWE1 (a ubiquitin ligase that can affect MUC expression via MIZ1) • Extent of LOH was positively correlated with the APOBEC signature (P = 0.039), loss of TP53 (P = 0.001), and presence of mutations in at least 1 of 15 genes involved in homologous recombination deficiency (P < 0.001)	• Of 63 driver genes: only TP53, TRAF3, and TGDS had an impact on outcome • Driver gene mutational burden leads to worse PFS/OS • Two markers of genomic instability were associated with outcomes: APOBEC mutational signature and LOH. Other studies have also shown APOBEC mutational signatures to be high risk [64] • Identified 9 separate copy number groupings with prognostic value ◦ Cluster 7: gain of 1q, t(4;14) and t(14;16) • No correlation between ISS stage and distribution of genetic features • On multivariate modeling: ◦ t(4;14) and biallelic TP53 inactivation predictive of PFS ◦ biallelic TP53 and CKS1B amplification predictive of OS ◦ "Double-Hit": median PFS 15.4 and OS 20.7 months ▪ biallelic inactivation of TP53 or ▪ ISS III with amplification of CKS1B:
Bolli et al. [8]	418	• 373 MM patients at diagnosis • Added 45 patients from a previously published WES study	• Many genes showed an excess of variants of possible oncogenic potential but unknown pathogenesis • FAT1, FAT3, FAT4, DNAH9, DNAH11, PCLO • Sporadic oncogenic mutations with potential clinical impact in CRBN and IKZF1^a • Possible novel tumor suppressors XBP1 and PRMDA which control plasma cell development • Frequently alleles of driver genes were multiply mutated -up to 5 for TP53- at a subclonal level • CCF of mutations did not influence OS save a trend towards improved OS for TP53 • Double hit^b frequently noted for TP53, CYLD, and TRAF3 mutations	• "Double Hit": ◦ both t(4;14) and PRDM1: median OS of 265 days ◦ t(4;14) and TP53 mutations: median OS of 228 days • Clusters of patients stratified based on the overall number of mutations and number/type of CAs that lead to distinct effects on survival ◦ Clusters predict PFS/OS: Cluster 2 showing the worse median OS—1973 days ◦ Cluster 2 was enriched for IGH translocations, the highest number of CAs, was enriched for amp(1q), del (13), del(17p), deletions of BIRC2/3 and XBP1 and carried more TP53 mutations • The only mutated gene with a clear prognostic impact on both PFS and OS was TP53, while DNAH11 mutations conferred worse OS only • Gene-level gains/losses: 5 events conferring shorter OS, including losses of TP53/17p, CYLD/16q, FAT1, and amplifications of MYC and NRAS • Multivariate analysis for PFS: mutations in SP140 and NRAS, t(4;14), amp(1q), del(17p13) and deletions of FAT1 and PRDM1 • Multivariate analysis for OS: t(4;14), amp(1q), del(17p13), del(1p)
MMRF CoMMpass Study [19, 85]	1151 in total	Data from patients receiving treatment in the context of clinical trials as well as with real word regimens were included	• 55 genes were significantly mutated and there was a 65% overlap with the MGP • The linker histones HIST1H1B, HIST1H1D, HIST1H1E, and HIST1H2BK all showed a distinctive pattern of missense mutations clustered in the highly conserved globular domain • FUBP1, an important regulator of MYC transcription, showed an excess of splice site and nonsense mutations, emerging as a potential tumor suppressor gene in MM	• Multivariate analysis for early PD^c ◦ TP53 mutation (OR, 3.78, P < 0.001) ◦ High lactate dehydrogenase levels (OR, 3.15, P=0.006), ◦ IgL-chain translocation (OR, 2.25, P = 0.033) ◦ IGLL5 mutation (OR, 2.15, P = 0.007) • A trend was found for gain(1q) and amp(1q) in regards to early PD; but this did correlate with early death within 24 months • Survival analysis revealed significantly shorter PFS in patients with greater than average somatic missense mutation load (49.3 vs. 72.6% 2-year PFS, P = 0.0023) and predicted expressed neoantigen load (N = 214, 55.5 vs. 72.9% 2-year PFS, P = 0.0028)

Number of patients

Source of patients

Genomic findings of note

High-risk factors identified

Myeloma genome Project [6, 17]

1273

• Myeloma XI trial,

• Dana-Faber Cancer Institute/Intergroupe Francophone du Myelome

• Multiple Myeloma Research Foundation CoMMpass study

• 63 driver genes identified including novel oncogenes PTPN11 (activator of MEK/ERK signaling), PRKD2 (protein kinase D), IDH1, and IDH2 (DNA methylation), and SF3B1 (spliceosome factor)

• Identified novel tumor suppressor genes including UBR5 (a ubiquitin ligase) and HUWE1 (a ubiquitin ligase that can affect MUC expression via MIZ1)

• Extent of LOH was positively correlated with the APOBEC signature (P = 0.039), loss of TP53 (P = 0.001), and presence of mutations in at least 1 of 15 genes involved in homologous recombination deficiency (P < 0.001)

• Of 63 driver genes: only TP53, TRAF3, and TGDS had an impact on outcome

• Driver gene mutational burden leads to worse PFS/OS

• Two markers of genomic instability were associated with outcomes: APOBEC mutational signature and LOH. Other studies have also shown APOBEC mutational signatures to be high risk [64]

• Identified 9 separate copy number groupings with prognostic value

◦ Cluster 7: gain of 1q, t(4;14) and t(14;16)

• No correlation between ISS stage and distribution of genetic features

• On multivariate modeling:

◦ t(4;14) and biallelic TP53 inactivation predictive of PFS

◦ biallelic TP53 and CKS1B amplification predictive of OS

◦ "Double-Hit": median PFS 15.4 and OS 20.7 months

▪ biallelic inactivation of TP53 or

▪ ISS III with amplification of CKS1B:

Bolli et al. [8]

418

• 373 MM patients at diagnosis

• Added 45 patients from a previously published WES study

• Many genes showed an excess of variants of possible oncogenic potential but unknown pathogenesis

• FAT1, FAT3, FAT4, DNAH9, DNAH11, PCLO

• Sporadic oncogenic mutations with potential clinical impact in CRBN and IKZF1^a

• Possible novel tumor suppressors XBP1 and PRMDA which control plasma cell development

• Frequently alleles of driver genes were multiply mutated -up to 5 for TP53- at a subclonal level

• CCF of mutations did not influence OS save a trend towards improved OS for TP53

• Double hit^b frequently noted for TP53, CYLD, and TRAF3 mutations

• "Double Hit":

◦ both t(4;14) and PRDM1: median OS of 265 days

◦ t(4;14) and TP53 mutations: median OS of 228 days

• Clusters of patients stratified based on the overall number of mutations and number/type of CAs that lead to distinct effects on survival

◦ Clusters predict PFS/OS: Cluster 2 showing the worse median OS—1973 days

◦ Cluster 2 was enriched for IGH translocations, the highest number of CAs, was enriched for amp(1q), del (13), del(17p), deletions of BIRC2/3 and XBP1 and carried more TP53 mutations

• The only mutated gene with a clear prognostic impact on both PFS and OS was TP53, while DNAH11 mutations conferred worse OS only

• Gene-level gains/losses: 5 events conferring shorter OS, including losses of TP53/17p, CYLD/16q, FAT1, and amplifications of MYC and NRAS

• Multivariate analysis for PFS: mutations in SP140 and NRAS, t(4;14), amp(1q), del(17p13) and deletions of FAT1 and PRDM1

• Multivariate analysis for OS: t(4;14), amp(1q), del(17p13), del(1p)

MMRF CoMMpass Study [19, 85]

1151 in total

Data from patients receiving treatment in the context of clinical trials as well as with real word regimens were included

• 55 genes were significantly mutated and there was a 65% overlap with the MGP

• The linker histones HIST1H1B, HIST1H1D, HIST1H1E, and HIST1H2BK all showed a distinctive pattern of missense mutations clustered in the highly conserved globular domain

• FUBP1, an important regulator of MYC transcription, showed an excess of splice site and nonsense mutations, emerging as a potential tumor suppressor gene in MM

• Multivariate analysis for early PD^c

◦ TP53 mutation (OR, 3.78, P < 0.001)

◦ High lactate dehydrogenase levels (OR, 3.15, P=0.006),

◦ IgL-chain translocation (OR, 2.25, P = 0.033)

◦ IGLL5 mutation (OR, 2.15, P = 0.007)

• A trend was found for gain(1q) and amp(1q) in regards to early PD; but this did correlate with early death within 24 months

• Survival analysis revealed significantly shorter PFS in patients with greater than average somatic missense mutation load (49.3 vs. 72.6% 2-year PFS, P = 0.0023) and predicted expressed neoantigen load (N = 214, 55.5 vs. 72.9% 2-year PFS, P = 0.0028)

CA cytogenetic abnormalities, CCF cancer clone fraction, IMID immunomodulatory drug, LOH loss of heterozygosity, MGP myeloma genome project, MM multiple myeloma, MMRF Multiple Myeloma Research Foundation, OS overall survival, PD progressive disease, PFS progression-free survival, WES whole-exome sequencing.

^aMutations in CRBN and IKZF1 have been associated with IMID resistance.

^bMutations in tumor suppressor genes co-occurred with deletion in the wild-type allele.

^cEarly progressive disease was defined as time to progression of less than 18 months.