Plasma cell myeloma / multiple myeloma

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Haematolymphoid Tumours (WHO Classification, 5th ed.)

editContent Update To WHO 5th Edition Classification Is In Process; Content Below is Based on WHO 4th Edition Classification
This page was converted to the new template on 2023-12-07. The original page can be found at HAEM4:Plasma Cell Myeloma.

Other relevent pages include: HAEM4:Plasma Cell Myeloma Variants

Note: author needs to include Plasma_Cell_Myeloma_Variants content in this page

(General Instructions – The focus of these pages is the clinically significant genetic alterations in each disease type. This is based on up-to-date knowledge from multiple resources such as PubMed and the WHO classification books. The CCGA is meant to be a supplemental resource to the WHO classification books; the CCGA captures in a continually updated wiki-stye manner the current genetics/genomics knowledge of each disease, which evolves more rapidly than books can be revised and published. If the same disease is described in multiple WHO classification books, the genetics-related information for that disease will be consolidated into a single main page that has this template (other pages would only contain a link to this main page). Use HUGO-approved gene names and symbols (italicized when appropriate), HGVS-based nomenclature for variants, as well as generic names of drugs and testing platforms or assays if applicable. Please complete tables whenever possible and do not delete them (add N/A if not applicable in the table and delete the examples); to add (or move) a row or column in a table, click nearby within the table and select the > symbol that appears. Please do not delete or alter the section headings. The use of bullet points alongside short blocks of text rather than only large paragraphs is encouraged. Additional instructions below in italicized blue text should not be included in the final page content. Please also see Author_Instructions and FAQs as well as contact your Associate Editor or Technical Support.)

Primary Author(s)*

  • Huan Mo, MD, MS
  • Zhenya Tang, MD, PhD

The University Of Texas MD Anderson Cancer Center, Department of Hematopathology, Houston, Texas

WHO Classification of Disease

Structure Disease
Book Haematolymphoid Tumours (5th ed.)
Category B-cell lymphoid proliferations and lymphomas
Family Plasma cell neoplasms and other diseases with paraproteins
Type Plasma cell neoplasms
Subtype(s) Plasma cell myeloma / multiple myeloma

WHO Essential and Desirable Genetic Diagnostic Criteria

(Instructions: The table will have the diagnostic criteria from the WHO book autocompleted; remove any non-genetics related criteria. If applicable, add text about other classification systems that define this entity and specify how the genetics-related criteria differ.)

WHO Essential Criteria (Genetics)*
WHO Desirable Criteria (Genetics)*
Other Classification

*Note: These are only the genetic/genomic criteria. Additional diagnostic criteria can be found in the WHO Classification of Tumours.

Related Terminology

(Instructions: The table will have the related terminology from the WHO autocompleted.)

Acceptable
Not Recommended

Gene Rearrangements

Put your text here and fill in the table (Instructions: Details on clinical significance such as prognosis and other important information can be provided in the notes section. Please include references throughout the table. Do not delete the table.)

Driver Gene Fusion(s) and Common Partner Genes Molecular Pathogenesis Typical Chromosomal Alteration(s) Prevalence -Common >20%, Recurrent 5-20% or Rare <5% (Disease) Diagnostic, Prognostic, and Therapeutic Significance - D, P, T Established Clinical Significance Per Guidelines - Yes or No (Source) Clinical Relevance Details/Other Notes
EXAMPLE: ABL1 EXAMPLE: BCR::ABL1 EXAMPLE: The pathogenic derivative is the der(22) resulting in fusion of 5’ BCR and 3’ABL1. EXAMPLE: t(9;22)(q34;q11.2) EXAMPLE: Common (CML) EXAMPLE: D, P, T EXAMPLE: Yes (WHO, NCCN) EXAMPLE:

The t(9;22) is diagnostic of CML in the appropriate morphology and clinical context (add reference). This fusion is responsive to targeted therapy such as Imatinib (Gleevec) (add reference). BCR::ABL1 is generally favorable in CML (add reference).

EXAMPLE: CIC EXAMPLE: CIC::DUX4 EXAMPLE: Typically, the last exon of CIC is fused to DUX4. The fusion breakpoint in CIC is usually intra-exonic and removes an inhibitory sequence, upregulating PEA3 genes downstream of CIC including ETV1, ETV4, and ETV5. EXAMPLE: t(4;19)(q25;q13) EXAMPLE: Common (CIC-rearranged sarcoma) EXAMPLE: D EXAMPLE:

DUX4 has many homologous genes; an alternate translocation in a minority of cases is t(10;19), but this is usually indistinguishable from t(4;19) by short-read sequencing (add references).

EXAMPLE: ALK EXAMPLE: ELM4::ALK


Other fusion partners include KIF5B, NPM1, STRN, TFG, TPM3, CLTC, KLC1

EXAMPLE: Fusions result in constitutive activation of the ALK tyrosine kinase. The most common ALK fusion is EML4::ALK, with breakpoints in intron 19 of ALK. At the transcript level, a variable (5’) partner gene is fused to 3’ ALK at exon 20. Rarely, ALK fusions contain exon 19 due to breakpoints in intron 18. EXAMPLE: N/A EXAMPLE: Rare (Lung adenocarcinoma) EXAMPLE: T EXAMPLE:

Both balanced and unbalanced forms are observed by FISH (add references).

EXAMPLE: ABL1 EXAMPLE: N/A EXAMPLE: Intragenic deletion of exons 2–7 in EGFR removes the ligand-binding domain, resulting in a constitutively active tyrosine kinase with downstream activation of multiple oncogenic pathways. EXAMPLE: N/A EXAMPLE: Recurrent (IDH-wildtype Glioblastoma) EXAMPLE: D, P, T


editv4:Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications).
Please incorporate this section into the relevant tables found in:
  • Chromosomal Rearrangements (Gene Fusions)
  • Individual Region Genomic Gain/Loss/LOH
  • Characteristic Chromosomal Patterns
  • Gene Mutations (SNV/INDEL)


Risk stratification of cytogenetic aberrations in plasma cell myeloma.

Table 4: Cytogenetic abnormalities on clinical course and prognosis in multiple myeloma (adapted from Rajan and Rajkumar 2015) [1][2]
Cytogenetic abnormality Smoldering plasma cell myeloma Plasma cell myeloma ***
Trisomies Intermediate risk of progression

Median TTP of 3 years

Standard-risk, median OS 7-10 years

Most have myeloma bone disease at diagnosis

Excellent response to lenalidomide-based therapy

t(11;14)(q13;q32) Standard risk of progression

Median TTP of 5 years

Standard-risk, median OS 7-10 years. See below.
t(6;14)(p21;q32) Standard risk of progression

Median TTP of 5 years

Standard-risk, median OS 7-10 years
t(4;14)(p16;q32) High risk of progression

Median TTP of 2 years

Intermediate-risk (mSMART) or high-risk (IMWG), median OS 5 years

Needs bortezomib-based initial therapy,

early ASCT (if eligible), followed by bortezomib-based

consolidation/maintenance

t(14;16)(q32;q23) Standard risk of progression

Median TTP of 5 years

High-risk, median OS 3 years

Associated with high levels of FLC and

25% present with acute renal failure as initial MDE

t(14;20)(q32;q11) Standard risk of progression

Median TTP of 5 years

High-risk, median OS 3 years
Gain(1q21) ** High risk of progression

Median TTP of 2 years

Intermediate-risk (mSMART) or high-risk (IMWG), median OS 5 years
Del(17p) * High risk of progression

Median TTP of 2 years

High-risk, median OS 3 years
Del(1p) N/A High-risk (mSMART) [3]
Trisomies plus any one of

the IgH translocations

Standard risk of progression

Median TTP of 5 years

May ameliorate adverse prognosis conferred by

high risk IgH translocations, and del 17p

Isolated monosomy 13,

or isolated monosomy 14

Standard risk of progression

Median TTP of 5 years

Effect on prognosis is not clear
Normal Low risk of progression

Median TTP of 7-10 years

Good prognosis, probably reflecting low tumor burden,

median OS >7-10 years

* Presence of del(17p) indicates high risk MM regardless of other abnormalities.

** Gain(1q21) (without other high risk abnormalities) is considered intermediate-risk.

*** Risk stratifications are according to IMWG and mSMART systems unless otherwise specified.

ASCT, autologous stem cell transplantation; IMWG, International Myeloma Working Group [4] ; mSMART, Mayo stratification for myeloma and risk-adapted therapy classification [5][2] ; MDE, myeloma-defining event; OS, overall survival; TTP, time to progression.

The case of t(11;14) - IGH/CCND1: [6]

  • Currently classified as a standard-risk abnormality.
  • However, with the advent of novel agents (including proteasome inhibitors, immunomodulatory agents, and, more recently, monoclonal antibodies[7][8][9]), findings from more recent retrospective reviews have shown that t(11;14) may be associated with intermediate outcomes in patients treated with novel agents as compared with patients who have standard- or high-risk cytogenetic aberrations [10][11].
  • Myeloma cells with t(11;14) have a unique biology, with relatively higher expression of the antiapoptotic protein BCL2 and lower expression of MCL1, in contrast to MM cells without this translocation. [12][13]
  • Venetoclax (BCL-2 inhibitor) mono-therapy has demonstrated anti-myeloma activity in patients with relapsed/refractory multiple myeloma positive for t(11;14).[6][14]


Role of cytogenetic aberrations in Staging of multiple myeloma. (Revised International Staging System)

Table 6: Staging systems for multiple myeloma[15]
Stage International Staging System Revised-ISS (R-ISS)
I Serum beta-2 microglobulin <3.5 mg/L,

Serum albumin ≥3.5 g/dL

ISS stage I and standard-risk chromosomal abnormalities by FISH

and

Serum LDH ≤ the upper limit of normal

II Not ISS stage I or III Not R-ISS stage I or III
III Serum beta-2 microglobulin ≥5.5 mg/L ISS stage III and either high-risk chromosomal abnormalities by FISH

or

Serum LDH > the upper limit of normal

Notes Standard-risk: No high-risk chromosomal abnormality.

High-risk: Presence of del(17p) and/or translocation t(4;14) and/or translocation t(14;16).

Survival data of plasma cell myeloma in clinical trial cohorts of selected cytogenetic aberrations are reviewed by Pieter Sonneveld et al. [4]

Gene expression signatures through high-throughput methods such as gene expression profiling (GEP) have been reported as being capable of discerning risk/prognosis in plasma cell myeloma. There are several GEP platforms available, such as 15-gene, 70-gene and 92-gene models, but they are not commonly used in clinical practice yet (NCCN guidelines 1.2021 for multiple myeloma). [16]

Gene mutations are also helpful for risk stratification in plasma cell myeloma, e.g., mutations of IRF4 or PRDM1 genes involving plasma cell differentiation are usually indicative for a favorable prognosis, while mutation of TP53, ATM or ATR genes involving DNA repair pathway mostly imply for a poor prognosis. [17]

End of V4 Section

Individual Region Genomic Gain/Loss/LOH

Put your text here and fill in the table (Instructions: Includes aberrations not involving gene rearrangements. Details on clinical significance such as prognosis and other important information can be provided in the notes section. Can refer to CGC workgroup tables as linked on the homepage if applicable. Please include references throughout the table. Do not delete the table.)

Chr # Gain, Loss, Amp, LOH Minimal Region Cytoband and/or Genomic Coordinates [Genome Build; Size] Relevant Gene(s) Diagnostic, Prognostic, and Therapeutic Significance - D, P, T Established Clinical Significance Per Guidelines - Yes or No (Source) Clinical Relevance Details/Other Notes
EXAMPLE:

7

EXAMPLE: Loss EXAMPLE:

chr7

EXAMPLE:

Unknown

EXAMPLE: D, P EXAMPLE: No EXAMPLE:

Presence of monosomy 7 (or 7q deletion) is sufficient for a diagnosis of AML with MDS-related changes when there is ≥20% blasts and no prior therapy (add reference).  Monosomy 7/7q deletion is associated with a poor prognosis in AML (add references).

EXAMPLE:

8

EXAMPLE: Gain EXAMPLE:

chr8

EXAMPLE:

Unknown

EXAMPLE: D, P EXAMPLE:

Common recurrent secondary finding for t(8;21) (add references).

EXAMPLE:

17

EXAMPLE: Amp EXAMPLE:

17q12; chr17:39,700,064-39,728,658 [hg38; 28.6 kb]

EXAMPLE:

ERBB2

EXAMPLE: D, P, T EXAMPLE:

Amplification of ERBB2 is associated with HER2 overexpression in HER2 positive breast cancer (add references). Add criteria for how amplification is defined.

Characteristic Chromosomal or Other Global Mutational Patterns

Put your text here and fill in the table (Instructions: Included in this category are alterations such as hyperdiploid; gain of odd number chromosomes including typically chromosome 1, 3, 5, 7, 11, and 17; co-deletion of 1p and 19q; complex karyotypes without characteristic genetic findings; chromothripsis; microsatellite instability; homologous recombination deficiency; mutational signature pattern; etc. Details on clinical significance such as prognosis and other important information can be provided in the notes section. Please include references throughout the table. Do not delete the table.)

Chromosomal Pattern Molecular Pathogenesis Prevalence -

Common >20%, Recurrent 5-20% or Rare <5% (Disease)

Diagnostic, Prognostic, and Therapeutic Significance - D, P, T Established Clinical Significance Per Guidelines - Yes or No (Source) Clinical Relevance Details/Other Notes
EXAMPLE:

Co-deletion of 1p and 18q

EXAMPLE: See chromosomal rearrangements table as this pattern is due to an unbalanced derivative translocation associated with oligodendroglioma (add reference). EXAMPLE: Common (Oligodendroglioma) EXAMPLE: D, P
EXAMPLE:

Microsatellite instability - hypermutated

EXAMPLE: Common (Endometrial carcinoma) EXAMPLE: P, T
editv4:Characteristic Chromosomal Aberrations / Patterns
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MOST OF THIS CAN BE TAKEN OUT AS IT IS REFLECTED IN THE TABLE. THE MATERIAL THAT IS RETAINED, PUT IN A BULLETED FORM.


INSERT AN ACTUAL TABLE. INCLUDE PREVALENCE AND OTHER RELEVANT INFO IN SEPARATE COLUMNS.

Numerical karyotype aberrations: [18][19]

  • Hyperdiploid/Trisomies plasma cell myeloma (≥47 and <75 chromosomes): It has been defined by multiple chromosomal gains, preferentially of the odd chromosomes 3, 5, 7, 9, 11, 15, 19 and 21.
  • Non-hyperdiploid plasma cell myeloma: It has a high frequency of IgH translocations (14q32), which are thought to be early events in the disease.
    • Hypodiploid (≤44 chromosomes),
    • Pseudodiploid (45–46 chromosomes)
    • Near tetraploid (>75 chromosomes), where the last is regarded to originate from doubling of the hypodiploid and pseudodiploid karyotypes.


Primary cytogenetic aberrations: These aberrations may be present both prior to and in plasma cell myeloma, indicating that these primary events can be identified in patients with non-IgM MGUS or smoldering multiple myeloma, the precursor states of plasma cell myeloma. [20][1]

  • Trisomies (commonly involving odd- numbered chromosomes) and hyperdiploidy
  • Immunoglobulin heavy chain (IgH) translocations and dysregulated oncogenes in the partner chromosome
    • t(4;14)/IGH/FGFR3 and MMSET
    • t(6;14)/IGH/CCND3
    • t(11;14)/IGH/CCND1
    • t(14;16)/IGH/MAF
    • t(14;20)/IGH/MAFB
    • IgH translocations with uncommon chromosome partners
  • Trisomies plus any IgH translocation

Common secondary cytogenetic aberrations: * [21][22][23][24]

  • del13q or - 13 **
  • del17p (TP53 deletion) or -17
  • del1p (loss of CDKN2C and TP73)
  • duplication or amplification of 1q (gain/amplification of CKS1B)

* Each secondary cytogenetic abnormality alone or in combination can occur in any primary molecular MM subtype.

** Del13q and -13 are considered as secondary events by the International Myeloma Working Group (IMWG), [24][20][1] but they are listed as primary events in other publications. [25][26]

Copy number alterations: According to genome-wide studies by array-based comparative genomic hybridization (aCGH), single nucleotide polymophism (SNP)–based CGH (SNP array) as well as massively parallel next generation sequencing NGS) of paired tumor/normal specimen from patients with diagnosed plasma cell myeloma, CNVs with a fluctuating frequency of <5 to >90% can involve both p and q arms of almost all chromosomes. Although their correlations with chromosomal abnormalities and their clinical significance are not well defined yet, the majority of these CNVs usually may indicate presence of additional aberrations that either routine chromosomal analysis have failed to detect or the concurrent FISH tests haven’t covered. [27][28][29]


End of V4 Section

Gene Mutations (SNV/INDEL)

Put your text here and fill in the table (Instructions: This table is not meant to be an exhaustive list; please include only genes/alterations that are recurrent or common as well either disease defining and/or clinically significant. If a gene has multiple mechanisms depending on the type or site of the alteration, add multiple entries in the table. For clinical significance, denote associations with FDA-approved therapy (not an extensive list of applicable drugs) and NCCN or other national guidelines if applicable; Can also refer to CGC workgroup tables as linked on the homepage if applicable as well as any high impact papers or reviews of gene mutations in this entity. Details on clinical significance such as prognosis and other important information such as concomitant and mutually exclusive mutations can be provided in the notes section. Please include references throughout the table. Do not delete the table.)

Gene Genetic Alteration Tumor Suppressor Gene, Oncogene, Other Prevalence -

Common >20%, Recurrent 5-20% or Rare <5% (Disease)

Diagnostic, Prognostic, and Therapeutic Significance - D, P, T   Established Clinical Significance Per Guidelines - Yes or No (Source) Clinical Relevance Details/Other Notes
EXAMPLE:EGFR


EXAMPLE: Exon 18-21 activating mutations EXAMPLE: Oncogene EXAMPLE: Common (lung cancer) EXAMPLE: T EXAMPLE: Yes (NCCN) EXAMPLE: Exons 18, 19, and 21 mutations are targetable for therapy. Exon 20 T790M variants cause resistance to first generation TKI therapy and are targetable by second and third generation TKIs (add references).
EXAMPLE: TP53; Variable LOF mutations


EXAMPLE: Variable LOF mutations EXAMPLE: Tumor Supressor Gene EXAMPLE: Common (breast cancer) EXAMPLE: P EXAMPLE: >90% are somatic; rare germline alterations associated with Li-Fraumeni syndrome (add reference). Denotes a poor prognosis in breast cancer.
EXAMPLE: BRAF; Activating mutations EXAMPLE: Activating mutations EXAMPLE: Oncogene EXAMPLE: Common (melanoma) EXAMPLE: T

Note: A more extensive list of mutations can be found in cBioportal, COSMIC, and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.

editv4:Gene Mutations (SNV/INDEL)
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THIS SECTION NEEDS REFERENCES.

Up to date, there is no known gene mutation which is considered as plasma cell myeloma-specific. However, a median mutation rate of approximately 1.6 mutations/Mb is observed in plasma cell myeloma cases, lower than that of approximately 10 mutations/Mb in melanoma and lung cancer cases. Table 3 adapted from report by Kumar and Rajkumar in 2018 summarizes the most common somatic mutations, their frequencies and major function (Table 2). Some of them are actionable mutations, e.g., KRAS and NRAS mutations.

SEE HCL PAGE FOR TABLE FORMAT. INSERT THE ADDITIONAL COLUMNS (E.G. TUMOR SUPPRESSOR/ONCOGENE).

Table 2. List of genes frequently mutated in plasma cell myeloma and their frequencies and main function [24]
Gene Mutation Effect Frequency Function
KRAS Activation 20-25% MAPK signaling pathway (cell survival and growth) [30][31]
NRAS Activation 23-25% MAPK signaling pathway (cell survival and growth); mutation may be associated with reduced sensitivity to bortezomib [32]
TP53 Complex [33] 8-15% Tumor suppressor involved in response to DNA damage and apoptosis
DIS3 [34] Unclear 11% Exosome endoribonuclease (RNA metabolism)
TENT5C (FAM46C) [35] Unclear ~11% Nucleotidyltransferase that act as a non-canonical poly(A) RNA polymerase which enhances mRNA stability and gene expression. [36]
BRAF [37] Activation 6-15% MAPK signaling pathway (cell survival and growth)
TRAF3 Loss of function 3-6% NF-κB signaling pathway (cell survival and proliferation) [38][39][40]
ROBO1 [41] Unclear 2-5% Transmembrane receptor for SLIT2; may involved in myeloma-marrow niche interaction [42]
CYLD [43] Loss of function 2-3% NF-κB signaling pathway (cell survival and proliferation) [44] and Wnt/β-catenin signaling [45]
EGR1 Unclear 4-6% Transcription factor; EGR1 interacts with JUN in modulating myeloma cell apoptosis [46]; the EGR1 mutation is associated with hyperdiploid cases and a better overall survival [47]
SP140 Unclear 5-7% Antigen-response mechanisms in mature B cells; only significantly mutated in the hyperdiploid samples [48]
FAT3 Unclear 4-7% Cadherin superfamily member (cell adhesion)
CCND1 Unclear 3% Cell cycle progression; CCND1 mutation occurs in t(11;14) cases and is associated with a poor prognosis when compared with non-mutated t(11;14) patients. [49]
End of V4 Section

Epigenomic Alterations

It has been reported that the translocation of t(4;14)(p16;q32) occurring in approximately 6 to 15% of all plasma cell myeloma cases causes a juxtaposition of two important genes, of FGFR3 and MMSET (also called as NSD2) adjacently located at 4p16 with the IGH enhancer located at 14q32, resulting in deregulation of FGFR3 and MMSET expressions. MMSET is functionally a methyl-transferase which plays an important role in the methylation of histone H3K36 and histone H4K20. The histone H3K36 modulates the expression of several genes, while the methylated histone H4K20 is involved in the recruitment of p53 binding protein 1 (53BP1) at the site of DNA damages. [50][51]

Genes and Main Pathways Involved

Put your text here and fill in the table (Instructions: Please include references throughout the table. Do not delete the table.)

Gene; Genetic Alteration Pathway Pathophysiologic Outcome
EXAMPLE: BRAF and MAP2K1; Activating mutations EXAMPLE: MAPK signaling EXAMPLE: Increased cell growth and proliferation
EXAMPLE: CDKN2A; Inactivating mutations EXAMPLE: Cell cycle regulation EXAMPLE: Unregulated cell division
EXAMPLE: KMT2C and ARID1A; Inactivating mutations EXAMPLE: Histone modification, chromatin remodeling EXAMPLE: Abnormal gene expression program
editv4:Genes and Main Pathways Involved
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Due to the wide spectrum of chromosomal abnormalities and somatic mutations identified in plasma cell myeloma, it’s believed that the oncogenesis and development of plasma cell myeloma may also involve many pathways. Please refer to review articles for more detailed information. [24][17]

NF-κB pathway: Dysregulation of NF-kB pathway is found in approximately 20% of patients, including the inactivation of TRAF2, TRAF3, CYLD, cIAP1/cIAP2, and activation of NFKB1, NFKB2, CD40, LTBR, TACI, and NIK that result primarily in constitutive activation of the non-canonical NF-kB pathway. [43] The anti-myeloma activity of proteasome inhibitor bortezomib (PS-341) may partly involve NF-kB pathway. [52][53]

RAS/MAPK pathway: This is the most frequently observed pathway mutations in plasma cell myeloma (~40%), including KRAS, NRAS, and BRAF. [47] In addition, FGFR3, one of the affected gene in t(4;14) rearrangement, is a tyrosine-kinase receptor that is on the upstream of RAS/MAPK pathway.

Cell-cycle pathway: This pathway include cyclin D (such as CCND1 and CCND3) and cyclin-dependent kinases (such as CDK4 and CDK6), as well as the inhibitors (such as CDKN2C and RB1). Many of these genes are commonly involved in cytogenetic aberrations. An early stage clinical trial suggests biologic activity of CDK4/6 inhibitor palbociclib in myeloma patients. [54]

DNA damage pathway: TP53 mutation and deletion (17p deletion) suggest a high risk disease. [55]

MYC activation: MYC rearrangement is found in 8% of the newly diagnosed myeloma patient in a Mayo Clinic study. It is associated with high disease burden and is an independent adverse prognostic factor. [56]

End of V4 Section

Genetic Diagnostic Testing Methods

Chromosomal analysis can detects abnormalities in only 30% of plasma cell myeloma cases at diagnosis, which are most likely due to the low proliferation of malignant plasma cells or myeloma cells and limit of availability of analyzable metaphase cells harvested from bone marrow culture. According to the updated American College of Medical Genetics and Genomics (ACMGG) technical standards and guidelines for chromosome studies in plasma cell dyscrasia, metaphase cells harvested from unstimulated 24- and 72-hour cultures as well as 120-hour IL-4-stimulated culture should be analyzed in each case. [57] However, longer bone marrow culture may potentially increase the risk of contamination, the occurrence of possible culture artifacts and/or the turnaround time (TAT). Conventional karyotyping is useful to detect hypodiploidy and deletion 13, but if FISH studies are done, additional value in initial risk‐stratification may be limited. [16]

CD138 enrichment: As recommended by ACMGG and the Cancer Genomics Consortium (CGC), bone marrow samples are subjected to be enriched for the CD138+ plasma cell fraction before applying for FISH and/CMA analyses, especially those with plasma cells percentage below a certain cutoff value for successful FISH and/or CMA analyses established by each laboratory. The enriched CD138+ plasma cells are usually not suitable for subsequently in vitro culture and chromosomal analysis. [58][59]

Fluorescence in situ hybridization (FISH) testing is performed mainly targeting clinically relevant abnormalities with well-known implication for risk stratification in plasma cell myeloma cases. The National Comprehensive Cancer Network (NCCN) recommends that a panel of FISH tests including t(4;14), t(11;14), t(14;16), t(14;20), del 1p, gain or amplification of 1q21, del 13, and del 17p13 should be performed for all active plasma cell myeloma cases at their initial workup (NCCN guideline Version 4.2021 for Multiple Myeloma). Identification of cytogenetic aberrations of a low frequency (e.g., del6q and del16q) by FISH is feasible not not routinely performed in the majority of clinical cytogenetic laboratories, mainly due to additional expenses and limit of clinical specimen.

For the follow-up specimens, the previously abnormal FISH tests may be repeated. Additional FISH tests for secondary aberration and disease progression can be performed (such as TP73/1q22, TP53/D17Z1 and MYC probes). [60]

In general, all these markers discussed above are not specifically for diagnosis of plasma cell myeloma and/or its precursors, MGUS and SMM. Instead, they are clinically applied for risk stratification and some of them, the actionable mutations, are also specifically utilized for choice of targeted and/or more efficient therapies.


Dr. Tang, Can you please verify the sensitivity numbers with our validation data? Also, can you add a comparison between marrow aspirate specimen and FFPE specimen in terms of assay specs?

A FISH test is considered very specific for the targeted aberration, but its sensitivity technically varies from 0.5% to 10% or higher (???). Depending on multiple factors such as type of FISH probes (fusion probe vs. break-apart probe), coverage of each probe, quality of test samples and so on.

Due to the extremely low levels of chromosomal abnormalities that are beyond the limit of detection by chromosomal analysis or FISH, high sensitive assays have been adopted for the evaluation of bone marrow aspirates for minimal residual disease (MRD), including multiparametric flow cytometry (MFC), allele-specific oligonucleotide (ASO)-qPCR and next-generation sequencing (NGS) of VDJ sequences to assess the status of MRD in plasma cell myeloma. [61]  


Chromosomal microarray (CMA) is more and more frequently applied in the clinical studies of plasma cell myeloma cases. This assay theoretically has a full coverage of the whole genome, mainly for copy number variations (CNVs) and possible copy number-neutral loss of heterozygosity (CN-LOH)     analyses of the whole genome. It is not able to detect balanced structural chromosomal abnormalities, such as translocation (e.g., IGH rearrangement–related), insertion and/or inversion. [62][63][64] In general, CMA analysis is not sensitive enough to identify any CNVs and/or CN-LOH at a low level, e.g., <25%). [64][58]


Table 3: Common FISH assays detecting chromosomal abnormalities in plasma cell neoplasms
Chr. Abnormalitites Target(s) Type of Probe
14q32.33 rearrangement IGH Break apart
t(11;14)(q13;q32) IGH/CCND1 Dual fusion
t(4;14)(p16;q32) IGH/FGFR3 or IGH/MMSET * Dual fusion
t(14;20)(q32;q11) IGH/MAFB Dual fusion
t(6;14)(p21;q32) IGH/CCND3 Dual fusion
t(14;16)(q32;q23) IGH/MAF Dual fusion
8q24.1 rearrangement MYC Break apart
17p- TP53 Deletion probes
1q21 amplification [65][66] and 1p deletion CKS1B and CDKN2C (P18) Amplification/deletion probes
-13/13q- RB1 and LAMP1 Deletion probes
+9/+15 Whole chromosomes Centromere Enumeration Probe
+3/+7 Whole chromosomes Centromere Enumeration Probe

* The FGFR3 probe poses a coverage of approximately 1 MB, including the whole FGFR3 and MMSET (NSD2) genes and their flanking region (https://www.molecular.abbott/int/en/chromosome/4).


Familial Forms

Family members and relatives of plasma cell myeloma patients have a high possibility (approximately 2-4 fold elevated risk) of developing the disease, implying for inherited predisposition. According to genome-wide association studies (GWAS), more than 10 genetic susceptibility loci associated with plasma cell myeloma have been identified, such as rs603965A (current id: rs9344) located at 11q13.3 within the CCND1 gene and rs4407910 located at 8q24.12. Please refer to review article by Manier et al for detailed information. [17]

Additional Information

  • None

Links

References

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  1. ↑ Jump up to: 1.0 1.1 1.2 Rajkumar, S. Vincent (2018). "Multiple myeloma: 2018 update on diagnosis, risk-stratification, and management". American Journal of Hematology. 93 (8): 1091–1110. doi:10.1002/ajh.25117. PMC 6223128. PMID 30400719.CS1 maint: PMC format (link)
  2. ↑ Jump up to: 2.0 2.1 Rajan, A M; et al. (2015). "Interpretation of cytogenetic results in multiple myeloma for clinical practice". Blood Cancer Journal. 5 (10): e365–e365. doi:10.1038/bcj.2015.92. ISSN 2044-5385. PMC 4635200. PMID 26517360.CS1 maint: PMC format (link)
  3. ↑ Hebraud, B.; et al. (2014-03). "Deletion of the 1p32 region is a major independent prognostic factor in young patients with myeloma: the IFM experience on 1195 patients". Leukemia. 28 (3): 675–679. doi:10.1038/leu.2013.225. ISSN 1476-5551. PMC 6140327. PMID 23892719. Check date values in: |date= (help)
  4. ↑ Jump up to: 4.0 4.1 Sonneveld, Pieter; et al. (06 16, 2016). "Treatment of multiple myeloma with high-risk cytogenetics: a consensus of the International Myeloma Working Group". Blood. 127 (24): 2955–2962. doi:10.1182/blood-2016-01-631200. ISSN 1528-0020. PMC 4920674. PMID 27002115. Check date values in: |date= (help)
  5. ↑ Cite error: Invalid <ref> tag; no text was provided for refs named :0
  6. ↑ Jump up to: 6.0 6.1 Paner, Agne; et al. (2020). "The evolving role of translocation t(11;14) in the biology, prognosis, and management of multiple myeloma". Blood Reviews. 41: 100643. doi:10.1016/j.blre.2019.100643.
  7. ↑ Dimopoulos, Meletios A.; et al. (2016). "Daratumumab, Lenalidomide, and Dexamethasone for Multiple Myeloma". New England Journal of Medicine. 375 (14): 1319–1331. doi:10.1056/NEJMoa1607751. ISSN 0028-4793.
  8. ↑ Palumbo, Antonio; et al. (2016). "Daratumumab, Bortezomib, and Dexamethasone for Multiple Myeloma". New England Journal of Medicine. 375 (8): 754–766. doi:10.1056/NEJMoa1606038. ISSN 0028-4793.
  9. ↑ Attal, Michel; et al. (2017). "Lenalidomide, Bortezomib, and Dexamethasone with Transplantation for Myeloma". New England Journal of Medicine. 376 (14): 1311–1320. doi:10.1056/NEJMoa1611750. ISSN 0028-4793. PMC 6201242. PMID 28379796.CS1 maint: PMC format (link)
  10. ↑ Kaufman, G P; et al. (2016). "Impact of cytogenetic classification on outcomes following early high-dose therapy in multiple myeloma". Leukemia. 30 (3): 633–639. doi:10.1038/leu.2015.287. ISSN 0887-6924.
  11. ↑ Kaufman, Jonathan L; et al. (2018). "Outcomes of Myeloma Patients with t(11;14) Receiving Lenalidomide, Bortezomib, and Dexamethasone (RVD) Induction Therapy". Blood. 132 (Supplement 1): 3282–3282. doi:10.1182/blood-2018-99-119051. ISSN 0006-4971.
  12. ↑ Touzeau, Cyrille; et al. (2018). "Targeting Bcl-2 for the treatment of multiple myeloma". Leukemia. 32 (9): 1899–1907. doi:10.1038/s41375-018-0223-9. ISSN 0887-6924.
  13. ↑ Touzeau, C; et al. (2014). "The Bcl-2 specific BH3 mimetic ABT-199: a promising targeted therapy for t(11;14) multiple myeloma". Leukemia. 28 (1): 210–212. doi:10.1038/leu.2013.216. ISSN 0887-6924. PMC 3887407. PMID 23860449.CS1 maint: PMC format (link)
  14. ↑ Kumar, Shaji; et al. (2017). "Efficacy of venetoclax as targeted therapy for relapsed/refractory t(11;14) multiple myeloma". Blood. 130 (22): 2401–2409. doi:10.1182/blood-2017-06-788786. ISSN 0006-4971.
  15. ↑ Palumbo, Antonio; et al. (2015). "Revised International Staging System for Multiple Myeloma: A Report From International Myeloma Working Group". Journal of Clinical Oncology. 33 (26): 2863–2869. doi:10.1200/JCO.2015.61.2267. ISSN 0732-183X. PMC 4846284. PMID 26240224.CS1 maint: PMC format (link)
  16. ↑ Jump up to: 16.0 16.1 Rajkumar, S. Vincent (05 2020). "Multiple myeloma: 2020 update on diagnosis, risk-stratification and management". American Journal of Hematology. 95 (5): 548–567. doi:10.1002/ajh.25791. ISSN 1096-8652. PMID 32212178 Check |pmid= value (help). Check date values in: |date= (help)
  17. ↑ Jump up to: 17.0 17.1 17.2 Manier, Salomon; et al. (02 2017). "Genomic complexity of multiple myeloma and its clinical implications". Nature Reviews. Clinical Oncology. 14 (2): 100–113. doi:10.1038/nrclinonc.2016.122. ISSN 1759-4782. PMID 27531699. Check date values in: |date= (help)
  18. ↑ Van Wier, Scott; et al. (2013-10). "Hypodiploid multiple myeloma is characterized by more aggressive molecular markers than non-hyperdiploid multiple myeloma". Haematologica. 98 (10): 1586–1592. doi:10.3324/haematol.2012.081083. ISSN 1592-8721. PMC 3789464. PMID 23716545. Check date values in: |date= (help)
  19. ↑ Debes-Marun, C. S.; et al. (2003-02). "Chromosome abnormalities clustering and its implications for pathogenesis and prognosis in myeloma". Leukemia. 17 (2): 427–436. doi:10.1038/sj.leu.2402797. ISSN 0887-6924. PMID 12592343. Check date values in: |date= (help)
  20. ↑ Jump up to: 20.0 20.1 Kumar, Shaji; et al. (2012). "Trisomies in multiple myeloma: impact on survival in patients with high-risk cytogenetics". Blood. 119 (9): 2100–2105. doi:10.1182/blood-2011-11-390658. ISSN 0006-4971. PMC 3311247. PMID 22234687.CS1 maint: PMC format (link)
  21. ↑ Gabrea, Ana; et al. (2006-09-08). "Distinguishing primary and secondary translocations in multiple myeloma". DNA repair. 5 (9–10): 1225–1233. doi:10.1016/j.dnarep.2006.05.012. ISSN 1568-7864. PMID 16829212.
  22. ↑ Schmidt-Hieber, Martin; et al. (2013-02). "Cytogenetic profiles in multiple myeloma and monoclonal gammopathy of undetermined significance: a study in highly purified aberrant plasma cells". Haematologica. 98 (2): 279–287. doi:10.3324/haematol.2011.060632. ISSN 1592-8721. PMC 3561437. PMID 22929983. Check date values in: |date= (help)
  23. ↑ Manier, Salomon; et al. (02 2017). "Genomic complexity of multiple myeloma and its clinical implications". Nature Reviews. Clinical Oncology. 14 (2): 100–113. doi:10.1038/nrclinonc.2016.122. ISSN 1759-4782. PMID 27531699. Check date values in: |date= (help)
  24. ↑ Jump up to: 24.0 24.1 24.2 24.3 Kumar, Shaji K.; et al. (07 2018). "The multiple myelomas - current concepts in cytogenetic classification and therapy". Nature Reviews. Clinical Oncology. 15 (7): 409–421. doi:10.1038/s41571-018-0018-y. ISSN 1759-4782. PMID 29686421. Check date values in: |date= (help)
  25. ↑ Manier, Salomon; et al. (02 2017). "Genomic complexity of multiple myeloma and its clinical implications". Nature Reviews. Clinical Oncology. 14 (2): 100–113. doi:10.1038/nrclinonc.2016.122. ISSN 1759-4782. PMID 27531699. Check date values in: |date= (help)
  26. ↑ Furukawa, Yusuke; et al. (2020-04). "Molecular basis of clonal evolution in multiple myeloma". International Journal of Hematology. 111 (4): 496–511. doi:10.1007/s12185-020-02829-6. ISSN 1865-3774. PMID 32026210 Check |pmid= value (help). Check date values in: |date= (help)
  27. ↑ Avet-Loiseau, Hervé; et al. (2009-09-20). "Prognostic significance of copy-number alterations in multiple myeloma". Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology. 27 (27): 4585–4590. doi:10.1200/JCO.2008.20.6136. ISSN 1527-7755. PMC 2754906. PMID 19687334.
  28. ↑ Walker, Brian A.; et al. (2010-10-14). "A compendium of myeloma-associated chromosomal copy number abnormalities and their prognostic value". Blood. 116 (15): e56–65. doi:10.1182/blood-2010-04-279596. ISSN 1528-0020. PMID 20616218.
  29. ↑ Lohr, Jens G.; et al. (2014-01-13). "Widespread genetic heterogeneity in multiple myeloma: implications for targeted therapy". Cancer Cell. 25 (1): 91–101. doi:10.1016/j.ccr.2013.12.015. ISSN 1878-3686. PMC 4241387. PMID 24434212.
  30. ↑ Wong, Kwan Yeung; et al. (09 10, 2018). "Frequent functional activation of RAS signalling not explained by RAS/RAF mutations in relapsed/refractory multiple myeloma". Scientific Reports. 8 (1): 13522. doi:10.1038/s41598-018-31820-9. ISSN 2045-2322. PMC 6131153. PMID 30201956. Check date values in: |date= (help)
  31. ↑ Shirazi, Fazal; et al. (08 18, 2020). "Activating KRAS, NRAS, and BRAF mutants enhance proteasome capacity and reduce endoplasmic reticulum stress in multiple myeloma". Proceedings of the National Academy of Sciences of the United States of America. 117 (33): 20004–20014. doi:10.1073/pnas.2005052117. ISSN 1091-6490. PMC 7443929 Check |pmc= value (help). PMID 32747568 Check |pmid= value (help). Check date values in: |date= (help)
  32. ↑ Mulligan, George; et al. (2014-01-30). "Mutation of NRAS but not KRAS significantly reduces myeloma sensitivity to single-agent bortezomib therapy". Blood. 123 (5): 632–639. doi:10.1182/blood-2013-05-504340. ISSN 1528-0020. PMC 4123425. PMID 24335104.
  33. ↑ Olivier, Magali; et al. (2010-01). "TP53 mutations in human cancers: origins, consequences, and clinical use". Cold Spring Harbor Perspectives in Biology. 2 (1): a001008. doi:10.1101/cshperspect.a001008. ISSN 1943-0264. PMC 2827900. PMID 20182602. Check date values in: |date= (help)
  34. ↑ Weißbach, Susann; et al. (2015-04). "The molecular spectrum and clinical impact of DIS3 mutations in multiple myeloma". British Journal of Haematology. 169 (1): 57–70. doi:10.1111/bjh.13256. ISSN 1365-2141. PMID 25521164. Check date values in: |date= (help)
  35. ↑ Zhu, Yuan Xiao; et al. (08 15, 2017). "Loss of FAM46C Promotes Cell Survival in Myeloma". Cancer Research. 77 (16): 4317–4327. doi:10.1158/0008-5472.CAN-16-3011. ISSN 1538-7445. PMC 5586597. PMID 28619709. Check date values in: |date= (help)
  36. ↑ Mroczek, Seweryn; et al. (09 20, 2017). "The non-canonical poly(A) polymerase FAM46C acts as an onco-suppressor in multiple myeloma". Nature Communications. 8 (1): 619. doi:10.1038/s41467-017-00578-5. ISSN 2041-1723. PMC 5606997. PMID 28931820. Check date values in: |date= (help)
  37. ↑ O'Donnell, Elizabeth; et al. (2013-08). "Targeting BRAF in multiple myeloma". Cancer Discovery. 3 (8): 840–842. doi:10.1158/2159-8290.CD-13-0297. ISSN 2159-8290. PMID 23928771. Check date values in: |date= (help)
  38. ↑ Mambetsariev, Nurbek; et al. (2016-01-26). "Nuclear TRAF3 is a negative regulator of CREB in B cells". Proceedings of the National Academy of Sciences of the United States of America. 113 (4): 1032–1037. doi:10.1073/pnas.1514586113. ISSN 1091-6490. PMC 4743771. PMID 26755589.
  39. ↑ Edwards, Shanique K. E.; et al. (2016-02). "Signaling mechanisms of bortezomib in TRAF3-deficient mouse B lymphoma and human multiple myeloma cells". Leukemia Research. 41: 85–95. doi:10.1016/j.leukres.2015.12.005. ISSN 1873-5835. PMC 4740239. PMID 26740054. Check date values in: |date= (help)
  40. ↑ Neja, Sultan Abda (2020-09). "The roles of TRAF3 mutation in the oncogenic progression and drug response of multiple myeloma". Genome Instability & Disease. 1 (5): 278–285. doi:10.1007/s42764-020-00022-x. ISSN 2524-7662. Check date values in: |date= (help)
  41. ↑ Bianchi, Giada; et al. (2019-11-13). "The Transmembrane Receptor Roundabout 1 (ROBO1) Is Necessary for Multiple Myeloma Proliferation and Homing to the Bone Marrow Niche". Blood. 134 (Supplement_1): 507–507. doi:10.1182/blood-2019-128778. ISSN 0006-4971.
  42. ↑ Bianchi, Giada; et al. (2016-12-02). "Roundabout 1 (ROBO1)/SLIT2 Is a Novel Signaling Pathway in Multiple Myeloma Promoting Survival and Bone Marrow Niche Interaction". Blood. 128 (22): 485–485. doi:10.1182/blood.V128.22.485.485. ISSN 0006-4971.
  43. ↑ Jump up to: 43.0 43.1 Keats, Jonathan J.; et al. (2007-08). "Promiscuous mutations activate the noncanonical NF-kappaB pathway in multiple myeloma". Cancer Cell. 12 (2): 131–144. doi:10.1016/j.ccr.2007.07.003. ISSN 1535-6108. PMC 2083698. PMID 17692805. Check date values in: |date= (help)
  44. ↑ Sun, S.-C. (2010-01). "CYLD: a tumor suppressor deubiquitinase regulating NF-kappaB activation and diverse biological processes". Cell Death and Differentiation. 17 (1): 25–34. doi:10.1038/cdd.2009.43. ISSN 1476-5403. PMC 5848464. PMID 19373246. Check date values in: |date= (help)
  45. ↑ van Andel, H.; et al. (04 2017). "Loss of CYLD expression unleashes Wnt signaling in multiple myeloma and is associated with aggressive disease". Oncogene. 36 (15): 2105–2115. doi:10.1038/onc.2016.368. ISSN 1476-5594. PMID 27775078. Check date values in: |date= (help)
  46. ↑ Chen, Lijuan; et al. (2010-01-07). "Identification of early growth response protein 1 (EGR-1) as a novel target for JUN-induced apoptosis in multiple myeloma". Blood. 115 (1): 61–70. doi:10.1182/blood-2009-03-210526. ISSN 1528-0020. PMC 2803692. PMID 19837979.
  47. ↑ Jump up to: 47.0 47.1 Walker, Brian A.; et al. (2015-11-20). "Mutational Spectrum, Copy Number Changes, and Outcome: Results of a Sequencing Study of Patients With Newly Diagnosed Myeloma". Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology. 33 (33): 3911–3920. doi:10.1200/JCO.2014.59.1503. ISSN 1527-7755. PMC 6485456. PMID 26282654.
  48. ↑ Walker, Brian A.; et al. (08 09, 2018). "Identification of novel mutational drivers reveals oncogene dependencies in multiple myeloma". Blood. 132 (6): 587–597. doi:10.1182/blood-2018-03-840132. ISSN 1528-0020. PMC 6097138. PMID 29884741. Check date values in: |date= (help)
  49. ↑ Walker, Brian A.; et al. (2015-04-23). "APOBEC family mutational signatures are associated with poor prognosis translocations in multiple myeloma". Nature Communications. 6: 6997. doi:10.1038/ncomms7997. ISSN 2041-1723. PMC 4568299. PMID 25904160.
  50. ↑ Martinez-Garcia, Eva; et al. (2011-01-06). "The MMSET histone methyl transferase switches global histone methylation and alters gene expression in t(4;14) multiple myeloma cells". Blood. 117 (1): 211–220. doi:10.1182/blood-2010-07-298349. ISSN 1528-0020. PMC 3037745. PMID 20974671.
  51. ↑ Pei, Huadong; et al. (2011-02-03). "MMSET regulates histone H4K20 methylation and 53BP1 accumulation at DNA damage sites". Nature. 470 (7332): 124–128. doi:10.1038/nature09658. ISSN 1476-4687. PMC 3064261. PMID 21293379.
  52. ↑ Hideshima, Teru; et al. (2009-07-30). "Bortezomib induces canonical nuclear factor-kappaB activation in multiple myeloma cells". Blood. 114 (5): 1046–1052. doi:10.1182/blood-2009-01-199604. ISSN 1528-0020. PMC 2721785. PMID 19436050.
  53. ↑ Hideshima, Teru; et al. (2002-05-10). "NF-kappa B as a therapeutic target in multiple myeloma". The Journal of Biological Chemistry. 277 (19): 16639–16647. doi:10.1074/jbc.M200360200. ISSN 0021-9258. PMID 11872748.
  54. ↑ Niesvizky, Ruben; et al. (2015). "Phase 1/2 study of cyclin-dependent kinase (CDK)4/6 inhibitor palbociclib (PD-0332991) with bortezomib and dexamethasone in relapsed/refractory multiple myeloma". Leukemia & Lymphoma. 56 (12): 3320–3328. doi:10.3109/10428194.2015.1030641. ISSN 1029-2403. PMID 25813205.
  55. ↑ Flynt, Erin; et al. (01 24, 2020). "Prognosis, Biology, and Targeting of TP53 Dysregulation in Multiple Myeloma". Cells. 9 (2). doi:10.3390/cells9020287. ISSN 2073-4409. PMC 7072230 Check |pmc= value (help). PMID 31991614. Check date values in: |date= (help)
  56. ↑ Abdallah, Nadine; et al. (2020-12-15). "Implications of MYC Rearrangements in Newly Diagnosed Multiple Myeloma". Clinical Cancer Research: An Official Journal of the American Association for Cancer Research. 26 (24): 6581–6588. doi:10.1158/1078-0432.CCR-20-2283. ISSN 1557-3265. PMID 33008815 Check |pmid= value (help).
  57. ↑ Mikhail, Fady M.; et al. (06 2016). "Section E6.1-6.4 of the ACMG technical standards and guidelines: chromosome studies of neoplastic blood and bone marrow-acquired chromosomal abnormalities". Genetics in Medicine: Official Journal of the American College of Medical Genetics. 18 (6): 635–642. doi:10.1038/gim.2016.50. ISSN 1530-0366. PMID 27124785. Check date values in: |date= (help)
  58. ↑ Jump up to: 58.0 58.1 Mikhail, Fady M.; et al. (09 2019). "Technical laboratory standards for interpretation and reporting of acquired copy-number abnormalities and copy-neutral loss of heterozygosity in neoplastic disorders: a joint consensus recommendation from the American College of Medical Genetics and Genomics (ACMG) and the Cancer Genomics Consortium (CGC)". Genetics in Medicine: Official Journal of the American College of Medical Genetics. 21 (9): 1903–1916. doi:10.1038/s41436-019-0545-7. ISSN 1530-0366. PMID 31138931. Check date values in: |date= (help)
  59. ↑ Mikhail, Fady M.; et al. (06 2016). "Section E6.1-6.4 of the ACMG technical standards and guidelines: chromosome studies of neoplastic blood and bone marrow-acquired chromosomal abnormalities". Genetics in Medicine: Official Journal of the American College of Medical Genetics. 18 (6): 635–642. doi:10.1038/gim.2016.50. ISSN 1530-0366. PMID 27124785. Check date values in: |date= (help)
  60. ↑ "PCPDS - Overview: Plasma Cell Proliferative Disorder, FISH, Bone Marrow". Mayo Clinic Laboratories.CS1 maint: display-authors (link)
  61. ↑ S, Kumar; et al. (2016). "International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma". Lancet Oncol. 17: e328–e346. PMID 27511158.
  62. ↑ Walker, Brian A.; et al. (2010-10-14). "A compendium of myeloma-associated chromosomal copy number abnormalities and their prognostic value". Blood. 116 (15): e56–65. doi:10.1182/blood-2010-04-279596. ISSN 1528-0020. PMID 20616218.
  63. ↑ Rack, Katrina; et al. (2016-01). "Genomic profiling of myeloma: the best approach, a comparison of cytogenetics, FISH and array-CGH of 112 myeloma cases". Journal of Clinical Pathology. 69 (1): 82–86. doi:10.1136/jclinpath-2015-203054. ISSN 1472-4146. PMID 26338801. Check date values in: |date= (help)
  64. ↑ Jump up to: 64.0 64.1 Pugh, Trevor J.; et al. (12 2018). "Assessing genome-wide copy number aberrations and copy-neutral loss-of-heterozygosity as best practice: An evidence-based review from the Cancer Genomics Consortium working group for plasma cell disorders". Cancer Genetics. 228-229: 184–196. doi:10.1016/j.cancergen.2018.07.002. ISSN 2210-7762. PMID 30393007. Check date values in: |date= (help)
  65. ↑ Hanamura, Ichiro; et al. (2006-09-01). "Frequent gain of chromosome band 1q21 in plasma-cell dyscrasias detected by fluorescence in situ hybridization: incidence increases from MGUS to relapsed myeloma and is related to prognosis and disease progression following tandem stem-cell transplantation". Blood. 108 (5): 1724–1732. doi:10.1182/blood-2006-03-009910. ISSN 0006-4971. PMC 1895503. PMID 16705089.
  66. ↑ Schmidt, Timothy M.; et al. (11 25, 2019). "Gain of Chromosome 1q is associated with early progression in multiple myeloma patients treated with lenalidomide, bortezomib, and dexamethasone". Blood Cancer Journal. 9 (12): 94. doi:10.1038/s41408-019-0254-0. ISSN 2044-5385. PMC 6877577. PMID 31767829. Check date values in: |date= (help)


Notes

*Primary authors will typically be those that initially create and complete the content of a page. If a subsequent user modifies the content and feels the effort put forth is of high enough significance to warrant listing in the authorship section, please contact the CCGA coordinators (contact information provided on the homepage). Additional global feedback or concerns are also welcome.

Acknowledgements:

We are grateful to Dr. Manisha Sutariya from Loma Linda University Health for providing additional information and guidance.

*Citation of this Page: “Plasma cell myeloma / multiple myeloma”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated 02/11/2025, https://ccga.io/index.php/HAEM5:Plasma_cell_myeloma_/_multiple_myeloma.

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