Compendium of Cancer Genome Aberrations

HAEM4Backup:Plasma Cell Myeloma

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GENERAL COMMENTS

  1. Please see author guidelines for all the sections starting with "Primary Authors" and ending with "Immunophenotype" and see the "Hairy cell leukemia" page as an example. All of these sections can be significantly trimmed down and bulleted. The goal of the CCGA is to provide clinically relevant molecular and cytogenetic information. Other sources are going to be much better for clinical and pathologic information, and we don't want to reproduce that work here. Hopefully, this will help reduce your work on future pages.
  2. Also, verbiage that closely resembles the WHO text can be removed due to potential legal issues pertaining to copyrights. Along the same lines, it would be best to cite primary literature, rather than the WHO.
  3. Remove table numbering and references to table numberings.
  4. Insert actual "wiki" tables, in places where you use tables
  5. In a few places in the text, smoldering myeloma is stated to be a "precursor" to plasma cell myeloma. However, it is more precise to refer to it as a plasma cell myeloma variant. Please correct me if I am wrong about this. If not, please adjust the wording.

Comment: The difference between PCM and smoldering PCM is the presence of additional myeloma defining events, such as end organ damage, higher cutoff of plasma cell percentage, or light train ratio. In NCCN, smoldering myeloma is also termed asymptomatic form (that is mainly observed unless in high risk patients), while PCM is termed symptomatic form (that is treated aggressively). Therefore, non-IgM MGUS, smoldering myeloma, solitary plasmacytoma of the bone, and PCM are the spectrum of stages/severities of one disease. In the WHO book, the allocation of sections of these diagnosis does not represent their biological nature. For example, the solitary plasmacytoma of the bone (related to myeloma) is a completely different disease from extraosseous plasmacytoma (related more to marginal zone lymphoma), but they are under a same section of plasmacytoma.


I make more specific comments below in bold and all caps.

Primary Author(s)*

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

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

Cancer Category/Type

Cancer Sub-Classification / Subtype

  • Plasma cell neoplasms (PCNs) [1]

Definition / Description of Disease [1][2][3]

  • A type of hematologic malignancy of monoclonal plasma cell
  • Originated from bone marrow but affecting multiple tissues and organs
  • Hallmarks: presence of M protein, neoplastic plasma (myeloma) cells and sign(s) of end-organ damages (CRAB:  hypercalcemia, renal insufficiency, anemia and bone lesions)

Synonyms / Terminology

  • Multiple myeloma
  • Medullary plasmacytoma
  • Myelomatosis
  • Myeloma, NOS
  • Kahler disease (no longer used)

Epidemiology / Prevalence [4][5]

  • Plasma cell myeloma accounts for approximately 1% of all types of malignant tumors, 10-15% of all hematologic malignancies
  • It is the third most common hematologic malignancies, next to lymphoma and leukemia
  • Incidence: 4 per 100,000 individuals per year
  • It’s estimated that 34,920 adults (19,320 men and 15,600 women) will be newly diagnosed with plasma cell myeloma and 12,410 patients (6,840 men and 5,570 women) will die from this disease in the United States in 2021.
  • It affects mostly adults with an age > 50 years (median age at diagnosis: 70 years). Young adults (<30 years) are infrequently and children (<16 years) are almost never affected by this disease.
  • Male : Female ratio: 1.1 : 1
  • Black : white ratio: 2 : 1
  • Current 5-year relative survival rate:  54%

Clinical Features [1][6][7]

  • A wide spectrum of clinical presentations: from asymptomatic (e.g., smoldering plasma cell myeloma) to highly aggressive with end-organ damages (e.g., one of more of CRAB presentations)
  • Bone pain can be the initial presentation in many cases
  • Pale appearance due to anemia and sometimes bleeding
  • Spinal cord compression due to vertebrae damages
  • Peripheral neuropathy
  • Infections due to compromised immunity can occur
  • Organomegaly
  • Skin lesions

Sites of Involvement [1][6][7]

  • Bone marrow, multifocal or generalized
  • Involvement of other organs and / or circulating plasma cells [8] may be secondarily but usually an indication of advanced disease (Is it ok? ~HM)
  • Extramedullary sites: bones, kidney, upper airway, skin and so on. (Extramedullary plasmacytoma is a different disease and it is closer to marginal zone lymphoma ~ HM)

Morphologic Features

Radiology findings: [9]

  • Osteolytic lesions are detected in approximately 70% of plasma cell myeloma cases on radiology skeletal survey, MRI and PET/CT. Other presentation such as osteoporosis, pathological bone fracture, and vertebral compression fracture can be observed as well. Vertebrae, ribs, skull, shoulders, pelvis and long bones are the sites frequently affected with bone lesion(s).

Macroscopy findings: [3]

  • During gross examination of severely affected bones, apparent defects filled with flesh-like hemorrhagic tissues can be observed.

Microscopy findings: [2][3][10]

  • Plasma cells in plasma cell myeloma can show mature and immature (or plasmablastic) forms. [11]
  • The mature plasma cells usually have eccentric nuclei, dense "clock face" chromatin, and abundant, deep basophilic (on Wright Giemsa stained marrow or cytological preparations) or amphophilic (on hematoxylin and eosin-stained histological sections) cytoplasm with a paranuclear hof.
  • Histologically, the monotypic plasma cells may present as interstitial, scattered distribution, in a form of small clusters and/or focal nodules. In advanced disease stages, the neoplastic plasma cells proliferate as diffuse sheets and replace normal bone marrow. [1]


Here I kept more detailed morphology descriptions ~HM


Differential diagnosis considerations may include:

  • Lymphoplasmacytic lymphoma (LPL, related to Waldenstrom macroglobulinemia, WM) and splenic/nodal marginal zone lymphoma can have extensive monotypic plasmacytic differentiation.
  • Mantle cell lymphoma (MCL) and a subset of plasma cell myeloma can share expressions of Cyclin D1 (CCND1) due to t(11;14)(q13;q32)(IGH/CCND1) translocation.
  • In the setting of plasmablastic morphology, differential diagnosis includes: anaplastic plasma cell myeloma, plasmablastic lymphoma, primary effusion lymphoma (PEL), ALK-positive large B-cell lymphoma, immunoblastic diffuse large B-cell lymphoma, and HHV8-positive diffuse large B-cell lymphoma NOS. [12]
  • Non-hematopoietic neoplasms with plasmacytoid morphology can also mimic plasma cell myeloma, such as plasmacytoid myoepithelioma of minor salivary glands [13], medullary thyroid carcinoma (or other neuroendocrine tumors) [14], and melanoma. It is important to keep in mind that CD138 is positive in many normal and neoplastic epithelial cells.

Immunophenotype


  • Plasma cell identification: For flow cytometry immunophenotyping, benign and neoplastic plasma cells can be identified with combined use of CD38 and CD138. [15] However, since anti-CD38 monoclonal antibodies (such as daratumumab) are used in myeloma therapy regimens, [16] the expression of CD38 on the residual myeloma cells can be decreased or negative on the marrow cells. It should be noted that plasma cells lose surface CD138 overtime after specimen procurement (such as from bone marrow aspirates); [17][18] therefore, delayed specimen processing will cause underestimated plasma cell percentage in flow cytometry immunophenotyping and lower yield in CD138 enrichment of plasma cell for cytogenetic studies. For immunohistochemical studies on Formalin-Fixed Paraffin-Embedded (FFPE) tissue sections, CD138 and MUM-1/IRF4 can be used to identify plasma cells.
  • Myeloma plasma cells: Unlike non-neoplastic plasma cells or plasma cells differentiated from lymphomas (especially marginal zone lymphoma and lymphoplasmacytic lymphoma), myeloma plasma cells often show aberrant loss of CD19 and CD45; they may also aberrantly express CD56, CD117, and/or Cyclin D1, which is associated with IGH/CCND1 translocation. For common aberrant immunophenotype patterns for myeloma cells, please see Flores-Montero et al. [19] The aberrancy of immunophenotypes of myeloma plasma cells can be used for minimal/measurable residual disease (MRD) detection in myeloma. [20][21][22]
  • Monoclonality: confirmed by immunoglobulin (Ig) light chain analysis, presenting as monotypic cytoplasmic immunoglobulin (cIg) expression but lack surface immunoglobulin (sIg). [17] On FFPE tissue sections, immunoglobulin light chain analysis on plasma cells can be assessed either by immunohistochemical stains or by chromogenic in situ hybridization (CISH).


Characteristic Chromosomal Aberrations / Patterns

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: [23][24]

  • 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. [25][26]

  • 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: * [27][28][29][30]

  • 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), [30][25][26] but they are listed as primary events in other publications. [31][32]

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. [33][34][35]


Gene Mutations (SNV/INDEL)

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 [30]
Gene Mutation Effect Frequency Function
KRAS Activation 20-25% MAPK signaling pathway (cell survival and growth) [36][37]
NRAS Activation 23-25% MAPK signaling pathway (cell survival and growth); mutation may be associated with reduced sensitivity to bortezomib [38]
TP53 Complex [39] 8-15% Tumor suppressor involved in response to DNA damage and apoptosis
DIS3 [40] Unclear 11% Exosome endoribonuclease (RNA metabolism)
TENT5C (FAM46C) [41] Unclear ~11% Nucleotidyltransferase that act as a non-canonical poly(A) RNA polymerase which enhances mRNA stability and gene expression. [42]
BRAF [43] Activation 6-15% MAPK signaling pathway (cell survival and growth)
TRAF3 Loss of function 3-6% NF-κB signaling pathway (cell survival and proliferation) [44][45][46]
ROBO1 [47] Unclear 2-5% Transmembrane receptor for SLIT2; may involved in myeloma-marrow niche interaction [48]
CYLD [49] Loss of function 2-3% NF-κB signaling pathway (cell survival and proliferation) [50] and Wnt/β-catenin signaling [51]
EGR1 Unclear 4-6% Transcription factor; EGR1 interacts with JUN in modulating myeloma cell apoptosis [52]; the EGR1 mutation is associated with hyperdiploid cases and a better overall survival [53]
SP140 Unclear 5-7% Antigen-response mechanisms in mature B cells; only significantly mutated in the hyperdiploid samples [54]
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. [55]

Epigenomics (Methylation)

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. [56][57]

Genes and Main Pathways Involved

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. [30][58]

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. [49] The anti-myeloma activity of proteasome inhibitor bortezomib (PS-341) may partly involve NF-kB pathway. [59][60]

RAS/MAPK pathway: This is the most frequently observed pathway mutations in plasma cell myeloma (~40%), including KRAS, NRAS, and BRAF. [53] 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. [61]

DNA damage pathway: TP53 mutation and deletion (17p deletion) suggest a high risk disease. [62]

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. [63]

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. [64] 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. [3]

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. [65][66]

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). [67]

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. [68]  


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. [69][70][71] In general, CMA analysis is not sensitive enough to identify any CNVs and/or CN-LOH at a low level, e.g., <25%). [71][65]


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 [72][73] 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).


Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications)

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) [26][74]
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) [75]
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 [76] ; mSMART, Mayo stratification for myeloma and risk-adapted therapy classification [1][74] ; MDE, myeloma-defining event; OS, overall survival; TTP, time to progression.

The case of t(11;14) - IGH/CCND1: [77]

  • Currently classified as a standard-risk abnormality.
  • However, with the advent of novel agents (including proteasome inhibitors, immunomodulatory agents, and, more recently, monoclonal antibodies[78][79][80]), 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 [81][82].
  • 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. [83][84]
  • Venetoclax (BCL-2 inhibitor) mono-therapy has demonstrated anti-myeloma activity in patients with relapsed/refractory multiple myeloma positive for t(11;14).[77][85]


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

Table 6: Staging systems for multiple myeloma[86]
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. [76]

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). [3]

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. [58]

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. [58]

Other Information

  • None

Links

References

(use "Cite" icon at top of page)

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 McKenna RW, et al., (2017). Plasma cell neoplasms, in World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, Revised 4th edition. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Arber DA, Hasserjian RP, Le Beau MM, Orazi A, and Siebert R, Editors. IARC Press: Lyon, France, p241-259.
  2. ↑ 2.0 2.1 Chng, W. J.; et al. (2014-02). "IMWG consensus on risk stratification in multiple myeloma". Leukemia. 28 (2): 269–277. doi:10.1038/leu.2013.247. ISSN 1476-5551. PMID 23974982. Check date values in: |date= (help)
  3. ↑ 3.0 3.1 3.2 3.3 3.4 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)
  4. ↑ Kumar, Shaji K.; et al. (2017-07-20). "Multiple myeloma". Nature Reviews. Disease Primers. 3: 17046. doi:10.1038/nrdp.2017.46. ISSN 2056-676X. PMID 28726797.
  5. ↑ American Cancer Society, Cancer Facts & Figures 2020,https://www.cancer.org/research/cancer-facts-statistics/all-cancer-facts-figures/cancer-facts-figures-2020.html
  6. ↑ 6.0 6.1 Rajkumar, S. Vincent (2016). "Updated Diagnostic Criteria and Staging System for Multiple Myeloma". American Society of Clinical Oncology Educational Book. American Society of Clinical Oncology. Annual Meeting. 35: e418–423. doi:10.1200/EDBK_159009. ISSN 1548-8756. PMID 27249749.
  7. ↑ 7.0 7.1 Moreau, Philippe; et al. (2021-03). "Treatment of relapsed and refractory multiple myeloma: recommendations from the International Myeloma Working Group". The Lancet. Oncology. 22 (3): e105–e118. doi:10.1016/S1470-2045(20)30756-7. ISSN 1474-5488. PMID 33662288 Check |pmid= value (help). Check date values in: |date= (help)
  8. ↑ Granell, Miquel; et al. (06 2017). "Prognostic impact of circulating plasma cells in patients with multiple myeloma: implications for plasma cell leukemia definition". Haematologica. 102 (6): 1099–1104. doi:10.3324/haematol.2016.158303. ISSN 1592-8721. PMC 5451342. PMID 28255016. Check date values in: |date= (help)
  9. ↑ Hillengass, Jens; et al. (2019-06). "International myeloma working group consensus recommendations on imaging in monoclonal plasma cell disorders". The Lancet. Oncology. 20 (6): e302–e312. doi:10.1016/S1470-2045(19)30309-2. ISSN 1474-5488. PMID 31162104. Check date values in: |date= (help)
  10. ↑ Rajkumar, S. Vincent; et al. (2014-11). "International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma". The Lancet. Oncology. 15 (12): e538–548. doi:10.1016/S1470-2045(14)70442-5. ISSN 1474-5488. PMID 25439696. Check date values in: |date= (help)
  11. ↑ Handa, U.; et al. (2010-06). "Plasma cell tumours: cytomorphological features in a series of 12 cases diagnosed on fine needle aspiration cytology". Cytopathology: Official Journal of the British Society for Clinical Cytology. 21 (3): 186–190. doi:10.1111/j.1365-2303.2009.0641.x. ISSN 1365-2303. PMID 19416310. Check date values in: |date= (help)
  12. ↑ Harmon, Charles M.; et al. (2016-10). "Plasmablastic Lymphoma: A Review of Clinicopathologic Features and Differential Diagnosis". Archives of Pathology & Laboratory Medicine. 140 (10): 1074–1078. doi:10.5858/arpa.2016-0232-RA. ISSN 1543-2165. PMID 27684979. Check date values in: |date= (help)
  13. ↑ Santos, Esaú P.; et al. (2011-12-12). "Plasmacytoid myoepithelioma of minor salivary glands: report of case with emphasis in the immunohistochemical findings". Head & Face Medicine. 7: 24. doi:10.1186/1746-160X-7-24. ISSN 1746-160X. PMC 3285037. PMID 22152025.
  14. ↑ Mehdi, Ghazala; et al. (2010-04). "FNAC diagnosis of medullary carcinoma thyroid: A report of three cases with review of literature". Journal of Cytology. 27 (2): 66–68. doi:10.4103/0970-9371.70745. ISSN 0974-5165. PMC 3001179. PMID 21157553. Check date values in: |date= (help)
  15. ↑ Rawstron, A. C.; et al. (2008). "Report of the European Myeloma Network on multiparametric flow cytometry in multiple myeloma and related disorders". Haematologica. 93 (3): 431–438. doi:10.3324/haematol.11080. ISSN 0390-6078.
  16. ↑ Palumbo, Antonio; et al. (2016-08-25). "Daratumumab, Bortezomib, and Dexamethasone for Multiple Myeloma". The New England Journal of Medicine. 375 (8): 754–766. doi:10.1056/NEJMoa1606038. ISSN 1533-4406. PMID 27557302.
  17. ↑ 17.0 17.1 Lin, Pei; et al. (2004). "Flow Cytometric Immunophenotypic Analysis of 306 Cases of Multiple Myeloma". American Journal of Clinical Pathology. 121 (4): 482–488. doi:10.1309/74R4-TB90-BUWH-27JX. ISSN 0002-9173.
  18. ↑ Kumar, Shaji; et al. (2010-09). "Immunophenotyping in multiple myeloma and related plasma cell disorders". Best Practice & Research. Clinical Haematology. 23 (3): 433–451. doi:10.1016/j.beha.2010.09.002. ISSN 1532-1924. PMC 3005703. PMID 21112041. Check date values in: |date= (help)
  19. ↑ Flores-Montero, Juan; et al. (2016). "Immunophenotype of normal vs. myeloma plasma cells: Toward antibody panel specifications for MRD detection in multiple myeloma: MM MRD ANTIBODY PANELS". Cytometry Part B: Clinical Cytometry. 90 (1): 61–72. doi:10.1002/cyto.b.21265.
  20. ↑ Flores-Montero, J; et al. (2017). "Next Generation Flow for highly sensitive and standardized detection of minimal residual disease in multiple myeloma". Leukemia. 31 (10): 2094–2103. doi:10.1038/leu.2017.29. ISSN 0887-6924. PMC 5629369. PMID 28104919.CS1 maint: PMC format (link)
  21. ↑ on behalf of the EuroFlow Consortium (EU-FP6, LSHB-CT-2006-018708); et al. (2012). "EuroFlow standardization of flow cytometer instrument settings and immunophenotyping protocols". Leukemia. 26 (9): 1986–2010. doi:10.1038/leu.2012.122. ISSN 0887-6924. PMC 3437409. PMID 22948490.CS1 maint: PMC format (link)
  22. ↑ B, Paiva; et al. (2020). "Measurable Residual Disease by Next-Generation Flow Cytometry in Multiple Myeloma". J Clin Oncol. 38: 784–792. PMID 31770060.
  23. ↑ 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)
  24. ↑ 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)
  25. ↑ 25.0 25.1 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)
  26. ↑ 26.0 26.1 26.2 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)
  27. ↑ 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.
  28. ↑ 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)
  29. ↑ 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)
  30. ↑ 30.0 30.1 30.2 30.3 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)
  31. ↑ 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)
  32. ↑ 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)
  33. ↑ 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.
  34. ↑ 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.
  35. ↑ 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.
  36. ↑ 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)
  37. ↑ 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)
  38. ↑ 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.
  39. ↑ 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)
  40. ↑ 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)
  41. ↑ 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)
  42. ↑ 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)
  43. ↑ 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)
  44. ↑ 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.
  45. ↑ 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)
  46. ↑ 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)
  47. ↑ 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.
  48. ↑ 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.
  49. ↑ 49.0 49.1 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)
  50. ↑ 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)
  51. ↑ 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)
  52. ↑ 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.
  53. ↑ 53.0 53.1 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.
  54. ↑ 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)
  55. ↑ 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.
  56. ↑ 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.
  57. ↑ 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.
  58. ↑ 58.0 58.1 58.2 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)
  59. ↑ 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.
  60. ↑ 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.
  61. ↑ 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.
  62. ↑ 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)
  63. ↑ 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).
  64. ↑ 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)
  65. ↑ 65.0 65.1 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)
  66. ↑ 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)
  67. ↑ "PCPDS - Overview: Plasma Cell Proliferative Disorder, FISH, Bone Marrow". Mayo Clinic Laboratories.CS1 maint: display-authors (link)
  68. ↑ 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.
  69. ↑ 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.
  70. ↑ 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)
  71. ↑ 71.0 71.1 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)
  72. ↑ 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.
  73. ↑ 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)
  74. ↑ 74.0 74.1 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)
  75. ↑ 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)
  76. ↑ 76.0 76.1 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)
  77. ↑ 77.0 77.1 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.
  78. ↑ 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.
  79. ↑ 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.
  80. ↑ 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)
  81. ↑ 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.
  82. ↑ 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.
  83. ↑ 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.
  84. ↑ 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)
  85. ↑ 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.
  86. ↑ 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)

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  1. Arber DA, et al., (2017). Acute myeloid leukaemia with recurrent genetic abnormalities, in World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, Revised 4th edition. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Arber DA, Hasserjian RP, Le Beau MM, Orazi A, and Siebert R, Editors. IARC Press: Lyon, France, p129-171.

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