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EMN recommendations on MM diagnosis and monitoring
newly diagnosed or relapsing MM.19,20 They recently monitored circulating MM cells at diagnosis and after induction therapy by multiparameter flow cytometry and confirmed inferior progression-free and overall survival for patients with persistent circulating MM cells before transplantation.21
Molecular studies
Cytogenetics
MM remains a heterogeneous disease with some patients progressing rapidly, while others survive more than 10 years. This clinical diversity is mainly driven by genetic abnormalities affecting the biological characteris- tics of MM cells.22 These alterations, summarized in Table 1, are important prognostic factors and can be divided into primary, disease-initiating abnormalities (hyper- diploidy and translocations involving the IGH locus) and secondary events, related to further progression of the disease.23 Fluorescence in situ hybridization on interphase cells, performed after purification of CD138+ cells or after counterstaining for the monoclonal light chains, is the technique required to detect these abnormalities.24 Alternative techniques that can be used are single- nucleotide polymorphism arrays, which are able to detect loss of heterozygosity and numerical chromosome abnor- malities, and comparative genomic hybridization arrays, which mainly reveal numerical abnormalities.
Up to 65% of patients with MM have translocations that involve the immunoglobulin heavy chain gene (IGH) on chromosome 14q32. The prevalence and prognostic impact of these IGH translocations vary according to the partner chromosome (Table 1). Hyperdiploidy generally consists of numerical gains (of the odd chromosomes)
with a few structural changes, and is usually associated with longer overall survival. Not all trisomies have the same prognostic impact: trisomy 21 impairs, while tri- somies 3 and 5 improve overall survival and may partially abrogate the negative impact of del17p and t(4;14).25
The most recurrent secondary alterations are dele- tion/monosomy of chromosome 13, deletion of chromo- some 17p13, chromosome 1 abnormalities (1p deletions and 1q gains/amplifications), and C-MYC translocations. Deletion 17p13 is considered the most detrimental prog- nostic factor (due to short remission after high-dose ther- apy and an increased incidence of extramedullary dis- ease) and is present in 8-10% of untreated patients.26 This deletion becomes clinically relevant when identified in the majority of PC. Different percentages (varying from 10%-60%) have been proposed to define a thresh- old that is associated with an impaired prognosis.27-29 The presence of a biallelic inactivation (i.e. by an additional mutation) of TP53 may particularly shorten overall sur- vival.30 Aberrations of chromosome 1 (either 1q21 gains/amplifications or deletions of 1p32) are common and associated with shorter progression-free and overall survival, particularly the less frequent del(1p32).31 Patients with adverse cytogenetics may have additional aberrations: in the British MRC IX trial patients with two adverse cytogenetic lesions had a median overall survival of 2 years, while the survival of patients with three aber- rations (an adverse IGH translocation, +1q21 and del17p13) was only 9 months.32 This inferior survival of patients with additional genetic abnormalities was also found in an Intergroupe Francophone du Myelome study that focused on patients with either del17p13 or t(4;14): for patients harboring t(4;14), multivariate analyses showed
Table 1. Recommended cytogenetic studies with implicated gene alterations and related prognosis.
Cytogenetics
Del17p13 P53
t(4;14)(p16.3;q32)
Gain 1q21 CKS1B
Del 1p32, Del 1p22
t(11;14)(q13;q32)
t(14;16)(q32;q23)
Hyperdiploidy of odd chromosomes
Genetic event Frequency
5-15% Independent marker,
FGR3 15% MMSET
34-40% Independent marker,
Prognosis
with negative impact on PFS and OS
Independent marker, with negative impact on PFS and OS
with negative impact on PFS and OS
Independent marker, with negative impact on PFS and OS
Good prognosis
Controversial
Standard prognosis, unless associated with other negative prognostic markers
Response to PI
Negative prognostic factor
Improves survival compared to classic agents
Negative prognostic factor
Negative prognostic factor
Good prognosis
Standard prognostic factor
Response to IMiD
Negative prognostic factor
Pomalidomide seems beneficial
Unfavorable for any IMiD
Negative prognostic factor
Good prognosis
Remarks
Most important prognostic factor
Ref
31, 60, 97
27, 98-100
Might be directly implicated in bortezomib resistance
CDKN2C
CCND1
CMAF
7-17%
20%
2-3%
60%
Sensitive
to venetoclax
101
102
103
Considered as a 104 negative prognostic
factor, but not confirmed in IFM study
May neutralize the 25 negative prognostic impact of del17p
or t(4;14)
PFS: progression free survival, OS overall survival, FGFR3: fibroblast growth factor receptor 3, MMSET: multiple myeloma SET domain, PI proteasome inhibitor, IMiD: immunomodulatory drug, CKS1B: CDC28 protein kinase regulatory subunit 1B, CDKN2C: cyclin-dependent kinase 4 inhibitor C, CCND1: cyclin-D1, MAF: musculoaponeurotic fibrosarcoma, IFM: Intergroupe Francophone du Myelome
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