Racial Differences in Molecular Cytogenetic Abnormalities in Black and White Patients with Multiple Myeloma (MM): A Single-Center Experience

Background: The incidence of MM is 2 to 3 fold higher in blacks than in whites; they present at a younger age and have better overall survival. The biological bases for these disparities remain unclear. Outcome of MM is linked to cytogenetic and molecular changes, both primary (hyperdiploidy and heavy chain (IgH) translocations) and secondary (rearrangements of MYC, activating mutations of NRAS, KRAS or BRAF, and deletions of 17p).

Methods: Cytogenomic alterations in consecutive MM patients were assessed using integration of metaphase chromosome analysis by GTG-banding and interphase fluorescence in situ hybridization (iFISH) in CD138-positive cells isolated from fresh BM samples using a protocol of magnetic-activated cell sorting. Changes evaluated included monosomy 13/del(13q), monosomy 17/del(17p), gain of 1q21, and rearrangements of the IGH gene including t(4;14), t(11;14) and t(14;16).

Results: Samples from 218 consecutive MM patients were analyzed (Table 1). 108 were from black and 110 were from white patients. Median age for blacks was 59 years (range: 36 - 82) and for whites, 63 years (range: 39 - 83) (p=0.008). Fewer black men than whites were observed (46.3% versus 64.6%, p=0.007). Overall, blacks had fewer abnormal karyotypes compared to whites (18.1% versus 31.8%; p=0.02). Black patients had a lower frequency of non-hyperdiploid karyotypes (8.5% versus 20.6%; p=0.01) and had a trend toward lower frequencies of rearrangements of IGH (30.8% versus 43.5%; p=0.055) than white patients. Most notably, they had significantly lower frequencies of monosomy 17/del(17p) (5.6% versus 18.5%; p=0.003) and monosomy 13/del(13q) (28.9% versus 46.3%; p=0.008).

After stratification by age (Figure 1), younger patients showed significantly higher frequencies of the monosomy 17/del(17p) abnormality (p=0.001) and the t(4;14) (p=0.04) than older patients, with the difference more significant in white patients. The associations among molecular cytogenetic abnormalities (Figure 2) showed a different association pattern for black and white patients. White patients with t(11;14) were more likely to have monosomy 13/del(13q) (p=0.003) and gain of 1q21 (p=0.02), while this association was not observed in black patients.

Conclusion: Black MM patients had significantly different cytogenetic profiles detected by iFISH on CD-138 selected malignant cells, compared to whites. Black MM patients had a more favorable profile, including lower frequencies of non-hyperdiploid karyotype and of IGH rearrangements. This study supports a biological basis for previously described outcome disparities between black and white patients with MM. Further studies will focus on identifying specific molecular targets and their impact on therapy and on overall outcome.

Table 1: Demographics and cytogenetic abnormalities of the MM patients

 

Demographics	Black	White	P-value#
Total, n	108	110
Gender, n (%)			=0.007*
Male	50     (46.30%)	71     (64.55%)
Female	58     (53.70%)	39     (35.45%)
Age (median)	59	63	=0.008*
Chromosome (karyotype)			=0.022*
Normal	86     (81.90%)	73     (68.22%)
Abnormal	19     (18.10%)	34     (31.78%)
Hyperdiploidy	8         (7.6%)	8         (7.4%)
Non-hyperdiploidy	9          (8.5%)	22       (20.6%)	=0.013*
11;14 translocation	2          (1.9%)	4         (3.7%)
FISH abnormality
-13/del(13q)	31     (28.97%)	50     (46.30%)	=0.008*
Gain of 1q21	35     (32.71%)	47     (43.52%)	=0.103
-17/del(17p)	6      (5.61%)	20     (18.52%)	=0.003*
IGH rearrangements	33     (30.84%)	47     (43.52%)	=0.055^
t(4;14)	7      (6.54%)	13     (12.38%)	=0.146
t(11;14)	15     (20.55%)	15     (19.48%)	=0.870
t(14;16)	2      (3.85%)	6      (10.71%)	=0.175
others	16     (14.95%)	15     (13.89%)	=0.824

*means statistical significant (p-value < 0.05), where ^ means marginal significant (0.05 < p-value < 0.10). #p-values come from the Cochran-Mantel-Haenszel tests for categorical variables, and t tests for continuous variables.

Figure 1: Distributions of cytogenetic abnormalities by age and race

 

 

Figure 2: Relationship of various cytogenetic abnormalities in the MM patients

Associations among eight molecular cytogenetic abnormalities. Each solid black line indicates one abnormality is statistically significantly associated with another abnormality.