Multiple myeloma classification

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Hannan Javed, M.D.[2]; Haytham Allaham, M.D. [3]; Shyam Patel [4]; Sima NoorAli, M.D.

Overview

Multiple myeloma can be classified into several subtypes based on the extent of organ involvement (medullary or extramedullary) and the disease clinical presentation (active symptomatic or smoldering asymptomatic). The four general categories include solitary plasmacytoma, monoclonal gammopathy of undetermined significance, smoldering multiple myeloma, and active multiple myeloma. Within the category of active multiple myeloma, the three risk groups include standard risk, intermediate risk, and high risk, based on the cytogenetic profile.

Classification

Multiple myeloma is still believed to be a single disease entity but it is a group of different cytogenetically distinct plasma cell malignancies. It can be classified on several basis.[1][2]

Biological genetic classification

Biological Genetic Classification
Hyperdiploid MM
  • Characterized by the presence of trisomies
  • Relatively indolent form of the disease
  • Relatively more favorable outcome
  • Slightly predominance among males
  • More common in elderly individuals
  • Higher incidence of MM bone disease
Non-hyperdiploid MM t(11;14)(q13;q32)
  • 15% of all MM cases
  • Subsequent upregulation of cyclin D1
  • Associated with expression of CD20 , lymphoplasmacytic morphology, hyposecretory disease, and lambda light chains
  • Majority of all cases of IgM MM
  • 50% of all cases of light chain amyloidosis
  • May be present in MGUS
  • Disease can be heterogeneous; global effect on prognosis neutral
t(4;14)(p16;q32)
  • Short remission duration after high-dose chemotherapy with stem cell support
  • New treatments to target the translocations (ie TKI-258) are under-development
  • Association with IgA heavy chains, lambda light chains, and chromosome 13 aberrations
  • Less common in patients with MGUS
  • Observed more frequently in patients with smoldering multiple myeloma
t(14;16)(q32;q23)
  • 5-7% of all MM patients
  • Association with higher frequency of chromosome 13 deletion
  • Association with IgA isotype
  • Aggressive clinical outcome
Chromosome 13 deletion
  • Significant as a marker now thought to be as a surrogate of its association with nh-MM
  • Detected in 50% of patients; 85% of chromosome 13 deletions are monosomy, and 15% interstitial deletions
  • Closely associated with other high-risk genetic features such as t(4;14)(p16;q32)
  • Almost 90% of cases with t(4;14)(p16;q32) will have chromosome 13 deletion

Molecular Cytogenetic Classification

Molecular Cytogenetic Classification
Hyperdiploid More favorable, IgG-k, older patients
Non-hyperdiploid

Aggressive, IgA-l, younger individuals

Cyclin D translocation t(11;14)(q13;q32) Upregulation of CCND1; favorable prognosis; bone lesions. Two subtypes by GEP
t(6;14q)(p21;32) Probably same as CCND1
t(12;14)(p13;q32) Rare
MMSET translocation t(4;14)(p16;q32) Upregulation of MMSET; upregulation of FGFR3 in 75%, unfavorable prognosis with conventional therapy; bone lesion less frequent
MAF translocation t(14;16)(q32;q23) Confirmed as aggressive by at least two series
t(14;20)(q32;q11) One series shows more aggressive disease
t(8;14)(q24;q32) Unknown effect on outcome but
Unclassified (other) Various subtypes and some with overlap
  • A more detailed version is given below:
Primary Molecular Cytogenetic Classification of Multiple Myeloma
Subtype Gene(s)/chromosomes affected Percentage of myeloma patients
Trisomic MM
  • Recurrent trisomies involving odd-numbered chromosomes with the exception of chromosomes 1, 13, and 21
42
IgH translocated MM
  • t(11;14) (q13;q32) CCND1 (cyclin D1)
  • t(4;14) (p16;q32) FGFR-3 and MMSET
  • t(14;16) (q32;q23) C-MAF
  • t(14;20) (q32;q11) MAFB
  • Other IgH translocations CCND3 (cyclin D3) in t(6;14) MM
30
Combined IgH translocated/trisomic MM
  • Presence of trisomies and any one of the recurrent IgH translocations in the same patient
15
Isolated Monosomy 14
  • Few cases may represent 14q32 translocations involving unknown partner chromosomes
4.5
Other cytogenetic abnormalities in absence of IgH translocations or trisomy or monosomy 14 5.5
Normal NA 3

Mayo Clinic Risk Stratification for Multiple Myeloma (mSMART)

  • Multiple myeloma can be classified according to risk status. The risk stratification for multiple myeloma consists of three groups, as follows:[1][3]
Mayo Clinic Risk Stratification for Multiple Myeloma (mSMART)
Risk group Chromosomal Abnormalities Frequency
Standard risk
  • t(11;14) (CCND1;IgH)
  • t(6;14) (CCND3;IgH)
  • Trisomies (chromosomes 3, 5, 7, 9, 11, 15, 19, 21)
  • Hyperdiploidy
75%
Intermediate Risk
  • t(4;14) (FGFR3;IgH)
  • Gain(1q21)
10%
High risk
  • t(14;16) (IgH;MAF)
  • t(14;20) (IgH;MAFB)
  • del(17p) (p53 deletion)
  • Non-hyperdiploidy
15%

References

  1. 1.0 1.1 Rajkumar SV (July 2016). "Multiple myeloma: 2016 update on diagnosis, risk-stratification, and management". Am. J. Hematol. 91 (7): 719–34. doi:10.1002/ajh.24402. PMC 5291298. PMID 27291302.
  2. Alexiou C, Kau RJ, Dietzfelbinger H, Kremer M, Spiess JC, Schratzenstaller B; et al. (1999). "Extramedullary plasmacytoma: tumor occurrence and therapeutic concepts". Cancer. 85 (11): 2305–14. PMID 10357398.
  3. Sonneveld P, Avet-Loiseau H, Lonial S, Usmani S, Siegel D, Anderson KC; et al. (2016). "Treatment of multiple myeloma with high-risk cytogenetics: a consensus of the International Myeloma Working Group". Blood. 127 (24): 2955–62. doi:10.1182/blood-2016-01-631200. PMC 4920674. PMID 27002115.

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