Table 2 High-risk molecular and cytogenetic subgroups; balanced translocations into the immunoglobulin heavy-chain locus and copy number abnormalities.

From: High-risk disease in newly diagnosed multiple myeloma: beyond the R-ISS and IMWG definitions

 

Prevalence

Pathogenesis

High risk per R-ISS, IMWG, mSMART:

Literature addressing prognosis:

Notes

t(14;20)a

1–2%

MAF upregulation including upregulation of cyclin D2, effects on cell interaction and upregulation of apoptosis resistance

mSMART

Inconsistent due to rarity

• Ross et al.: median OS 14.4 months [11]

• Jurczyszyn et al.b: median PFS 30 months [56]

• Shah et al. [57]: HR for OS of 1.90 (P = 0.0089) with only del(17p) showing worse prognosis

No large databases, cohorts of less than 50 patients

Frequently found with other high-risk cytogenetic abnormalities: del(17p), t(4;14), t(14;16), del(13q), non-hyperdiploid karyotype

t(14;16)

1–2%

MAF upregulation including upregulation of cyclin D2

Effects on cell interaction and upregulation of apoptosis resistance

R-ISS mSMART

Inconsistent due to rarity:

• Jurczysyn et al.c: median PFS 31 months; 5-year OS 55% [56]

• Mayo Clinic and Medical Research Council group [58] showing poor outcomes

• IFM studies showed neutral outcomes [59]

Data from Jurczysyn et al. do not vary significantly from R-ISS stage III outcomes.

Of note, the R-ISS did not report specifically on outcomes of t(14;16) patients

t(4;14)

15%

MMSET on der(4) MMSET is known to have histone methyltransferase activity and is deregulated early on in the genesis of developing MMd [9]

IMWG R-ISS mSMART

• Chan et al.: PFS of 33.5 months for 75 patients [60]

• Mayo group has demonstrated improved median OS ~ 4–5 years [55]

• Bolli et al.: On MV analyses, t(4;14) predicted both PFS and OS independently of other CAs [8]

• Compared to standard-risk patients who achieve median OS ~10 years, t(4;14) patients remain bad actors

• Some frequently associated chromosomal changes worsen t(4;14) such as +1q, 1p32 and potentially 13q deletions

t(8;14) and MYC translocations

1–2%

Upregulation of the oncogene MYCe

none

• Myeloma IX trial: those with a MYC translocation had inferior PFS and OS on MV analyses [61]

• CoMMpass study [22]: Only IgL-MYC translocations had worse PFS and OSf

Significant associations between Myc and other abnormalities highlight oncogenic dependencies

Myc rearrangements can lead to deregulation of FAM46C which has been associated with hyperdiploid MM [17]

t(11;14)

15–20%

Upregulation of CCND1 [62] expressiong

Express higher ratios of BCL2 (anti-apoptotic) to MCL1 (proapoptotic)

None

• Traditionally favorable/standard risk

• Recent reports show t(11;14) is likely at best standard risk [63]

• Connect MM registry data shows neutral risk but possibly increased risk in AA patients [64]

• Mutations in CCND1 are key with poor survival amongst mutated v non-mutated t(11;14) patients: median OS 20.2 months vs. NR (P = 0.005) in the Myeloma XI trial [65]

t(11;14) associated with a characteristic lymphoplasmacytic morphology, light chain MM, rarer variants of MM (IgD, IgM, and nonsecretory), and expression of CD20 on the surface of PCs [66]

t(14;x)h

15–20%

Unknown

None

• Mao et al. [67]: t(14;x) lead to improved OS on MV analyses (HR = 0.51, 95% CI 0.30–0.85)

• Kaufman et al. [68]: t(14;x) median PFS 26.6 and OS 92.8 months, not significantly different from the comparison general cohort

Despite its remarkable prevalence with t(14;unknown) being as common as t(4;14) or t(11;14), its impact on risk and prognosis is not well described albeit it is thought to be neutral

+1q

Overall: ~33%

Gain: ~21.9%

Amp: ~6.3%

Amplified CKS1B results in greater degradation of p27, activation of the Cdk/cyclin complex, and cell cycle upregulation by promoting the G1/S transition [13]

None

• Giri et al. [69]: 3578 NDMM patients, any chromosome 1 abnormality inferior OS (median OS 46.6 vs. 70.1 months)

• Shah et al. [57]: UK Myeloma XI and IX trials, 1q gain inferior OS (HR 1.67; P = 3.30 × 10–5); amp 1q worse (HR 2.28; P = 2.32 × 10− 6)

• MGP: both gain and amp of CKS1B associated with decreased PFS and OS [6] but amp worse

• Gain and amp have been shown to impact OS in other cohorts [8, 14, 19, 26, 57]

Cutoff for a positive test remains controversial with the EMN 20% definition frequently employed but higher CCF may impact outcomes. An et al. showed that amongst patients with 1q21 gains a 20% CCF predicted PFS and OS but stratifying by increasing CCF had no impact on outcomes and likely at 20% CCF cutoff remains appropriate [70]

1p-

~10%

Deletion of CDKN2C, a tumor suppressor gene, leads to deregulation of the G1/S transition

FAM46C promotes MM cell growth-inhibiting apoptosis

None

• Myeloma IX trial: inferior OS for both CDKN2C mutation at 1p32.3 as well as FAM46C at 1p12 [71]

• IFM collection: In MV analyses of 1195 patients, 1p22 and 1p32 deletions both showed inferior OS [72]

Amplification of CKS1B is frequently associated with the deletion of the CDKN2C gene at the chromosome 1p32.3 (1p-) locus

del 13q/-13

del(13q): ~5%

Monsomy 13: 35%

FISH probes to both putative tumor suppressor gene Rb-1 and to D13S319, a gene locus distal to Rb-1, showed inferior OS in NDMM patients. Exact mechanism though is unclear.

None

• Early studies showed inferior OS in NDMM patients but this may be due to co-occurring high-risk CAs [73]

• In 1181 NDMM patients, on MV analyses monosomy 13 lead to worse OS with a HR of 1.27 (P = 0.022) while del(13q) with a HR of 0.48 (P = 0.006) [74]

• Deletions and abnormalities involving chromosome 13 were one of the earliest recognized high-risk features in NDMM [75]

• Up to 90% of patients with t(4;14) have deletion 13q [76]

• CCF has not been clearly defined, at CCF >25% it is likely co-occurring CAs, particularly t(4;14) and del(17p), drive poor clinical outcomes [70]

del17p

5–10%

Tumor suppressor gene but the exact mechanism by which del17p promotes aggressive disease biology remains unclear

R-ISS

IMWG

mSMART

Extensive data, see the manuscript as well as Table 3 [26]

TP53 induces clonal immortalization and survival of tumor cells as well as drug resistance which is thought to drive poor prognosis [77, 78]

  1. amp amplification, ≥4 copies, AA African American, CA cytogenetic abnormalities, CCF cancer clone fraction, EMN European myeloma network, HR hazard ratio, IFM Institut Francophone du Mye´lome, IMWG international myeloma working group, MGP myeloma genome project, MV multivariate, NDMM newly diagnosed multiple myeloma, NR not reached, OS overall survival, PCs plasma cells, PFS progression-free survival, Rb-1 retinoblastoma gene-1, R-ISS revised international staging system.
  2. aWhile t(4;14) and translocation t(14;16) are included as high-risk chromosomal abnormalities in the R-ISS, other chromosome 14 translocations including t(14;20) are not but have been shown to be unfavorable.
  3. bFive clinical centers in Germany, Italy, and the United States.
  4. cIn total, 213 patients with t(14;16) from 24 clinical centers in Germany, Italy, Spain, Israel, Poland, Romania, Czech Republic and the United States.
  5. dThe karyotypically silent t(4;14) translocation, undetectable by conventional cytogenetic analysis, was identified first based on breakpoints on chromosome 4 in the FGFR3 gene and subsequently involving the MMSET gene (MMSET: multiple myeloma SET domain; also known as Wolf-Hirschhorn syndrome candidate 1 (WHSC1) or nuclear receptor-binding SET domain 2 (NSD2)). The t(4:14) translocation was the first example of an IgH translocation that simultaneously dysregulated two genes with oncogenic potential: FGFR3 on der(14) and MMSET on der(4). Importantly, FGFR3 shows only weak transforming activity and is eventually lost in 30% of patients suggesting that it is not the main oncogenic factor [76], whereas MMSET is known to have histone methyltransferase activity and is deregulated early on in the genesis of developing myeloma [12].
  6. eTranslocations at 8q24 have been shown to portend to poor outcomes and 8q24 breakpoints have been found to partner with immunoglobulin enhancers (IGH, IGK, and IGL), important B-cell maturation loci including (XBP1, FAM46C, CCND1, KRAS) and other superenhancers, such as NSMCE2, TXNDC5, FOXO3, IGJ, and PRDM1 [22, 61].
  7. fThese data indicate that aberrant MYC expression resulting from MYC amplification or translocation is a common feature of myeloma, but the IgL-MYC translocated subset is unique among MYC alterations in that it portends a very poor prognosis. On the CoMMpass study, patients with an IgL translocation did not benefit from IMiD-containing therapies that target the lymphocyte-specific transcription factor Ikaros which is bound at high levels to the IgL enhancer. Also, 78% of IgL-MYC translocations co-occur with hyperdiploid disease, a marker of standard risk, suggesting that IgL-MYC-translocated myeloma is being misclassified.
  8. gNormal B-cells express cyclin D2 and D3 [62].
  9. ht(14;x) The partner genes translocated with the IgH vary in their impact on risk and prognosis in NDMM patients. Not infrequently the IgH spilt can be detected by FISH but no specific partner chromosomes can further be identified [68].
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