International Myeloma Working Group (IMWG) Molecular Classification of Multiple Myeloma

The intent of this statement is to provide a biological classification of multiple myeloma and to establish the prognostic value of known genetic factors.

Myeloma is divided at the highest genetic level into two subtypes: disease that is hyperdiploid (h-MM), and disease that is non-hyperdiploid (nh-MM). The non-hyperdiploid type is characterized by immunoglobulin heavy-chain (IgH) translocations and is generally associated with more aggressive disease and shorter survival.

Accurate prognostic determination of disease course allows for a more rational selection and sequencing of therapy approaches and more direct discussion with the patient regarding disease threat. Risk stratification is essential for better understanding of the composition of patients in clinical trials, and also allows, to some degree, cross-comparison of different clinical trial populations.

Testing Recommendations

• At a minimum, baseline genetic information should be obtained in all MM cases
• Testing must be done with either cytoplasmic immunoglobulin-enhanced FISH or FISH carried out on the nuclei from purified plasma cells
• Minimum FISH panel should include t(4;14)(p16;q32), t(14;16)(q32;q23), and 17p13 deletions
• More comprehensive panel should include testing for t(11;14)(q13;q32), chromosome 13 deletion, ploidy category, and chromosome 1 abnormalities
• At a minimum, all clinical trials should consider incorporation of GEP

Disease sub-types
Hyperdiploid

• Characterized by trisomies
• More indolent form of the disease
• Tendency toward more favorable outcome
• Slightly more common among males
• More common in elderly individuals
• Higher incidence of MM bone disease

Non-hyperdiploid (higher-risk) myeloma, with the exception of t(11;14(q13;q32), which is good risk:

• t(11;14)(q13;q32)
  • 15% of MM patients
  • consequent upregulation of cyclin D1
  • associated with CD20 expression, lymphoplasmacytic morphology, hyposecretory disease, and lambda light chains
  • majority of all cases of IgM MM
  • one half of all cases of light chain amyloidosis
  • can be observed 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) being developed
  • associated with IgA heavy chains, lambda light chains, and chromosome 13 abnormalities
  • less common in patients with MGUS
  • present more frequently in patients with SMM (smoldering multiple myeloma)
• t(14;16)(q32;q23)
  • 5-7% of all MM cases
  • associated with higher frequency of chromosome 13 deletion
  • associated with IgA isotype
  • more aggressive clinical outcome
• Chromosome 13 deletion
  • Significance 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 like t(4;14)(p16;q32)
  • Nearly 90% of cases with t(4;14)(p16;q32) will harbor chromosome 13 deletion

Secondary genetic events that reflect disease progression
Monoclonal plasma cells can undergo different stages of evolution over time; it has not been well defined what the specific steps associated with disease progression are. Genetic abnormalities that reflect progression include:

• Deletion of 17p13
  • Most important cytogenetic factor for prognostication
  • Locus of the tumor-suppressor gene, p53
  • Very negative effect on survival
  • Predicts for shorter survival, more aggressive disease, higher prevalence of extramedullary disease, hypercalcemia, short duration of response post-HDT, and CNS involvement
  • Most cases of plasma cell leukemia (primary and secondary) have p53 abnormalities
  • Uncommon in MGUS
• Chromosome 1 abnormalities (1p deletion and 1q amplification)
  • Abnormalities in both short and long arms of chromosome 1 associated with shorter survival
  • GEP signature for high-risk disease

mSMART Classification
Another method of interpreting the significance of genetic mutations in myeloma has been published by the Mayo group as mSMART 2.0²

High-Risk	Intermediate Risk	Standard-Risk
FISH	FISH	All others, including
Del 17p	t(4;14)	hyperdiploid
t(14;16)	Cytogenetic deletion 13 or hypodiploidy	t(11;14) t(6;14)
t(14;20)
GEP High-risk signature	Plasma Cell Labeling Index > 3%

• Note that intermediate- and standard-risk patients with these factors will be classified as high-risk by GEP
• Standard-risk patients with LDH>ULN and beta2M>5.5 may indicate worse prognosis
• Prognosis is worse when t(4;14) is associated with high beta2M and anemia
• T(11;14) may be associated with plasma cell leukemia

Recommended FISH testing and association with outcome

Essential testing	FISH Tests	Testing Frequency
Established markers	T(4;14)(p16;q32)	Once
	T(14;16)(q32;q23)	Once
	17p13	May be repeated
Expanded panel; markers with modest effects	Hyperdiploidy	Once
Other markers	T(11;14)(q13;q32)	Once
	Chromosome 13	May be repeated
	Other translocations	Once
Chromosome 1	1q amplification, 1p deletion	May be repeated
aCGH-derived markers	12p deletion, 5q amplification	May be repeated

Emerging Genetic Tests: clinical and research recommendations

Level	FISH Tests	Testing Frequency
Established markers	Minimal FISH panel (clinic)	Once (baseline)
	GEP	May be repeated
Suggested tests	aCGH/SNP	Once
	Predictive markers	Once
	Serial GEP	Repeated

New proposed IMWG molecular cytogenetic classification

	Percentage of patients	Clinical & lab features
Hyperdiploid	45	More favorable, IgG-kappa, older patients
Non-hyperdiploid	40	Aggressive, IgA-lambda, younger individuals
Cyclin D translocation	18
t(11;14)(q13;q32)	18	Upregulation of CCND1; favorable prognosis; bone lesions. Two subtypes by GEP
t(6;14q)(p21;32)	2	Probably same as CCND1
t(12;14)(p16;q32)	<1	Rare
MMSET translocation	15
t(4;14)(p16;q32)	15	Upregulation of MMSET; upregulation of FGFR3 in 75%; unfavorable prognosis with conventional therapy; bone lesions less frequent
MAF translocation	8	Aggressive
t(14;16)(q32;q23)	5	Confirmed as aggressive by at least two series
t(14;20)(q32;q11)	2	One series shows more aggressive disease
t(8;14)(q24;q32)	1	Unknown effect on outcome, but presumed aggressive
Unclassified (other)	15	Various subtypes and some with overlap

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¹R. Fonseca et al. International Myeloma Working Group molecular classification of multiple myeloma: spotlight review. Leukemia(2009) 23, 2210-2221.

²Kumar et al. Mayo Clin Proc 2009 84:1095-1110, Revised and updated: June 2010