Clinical Significance of Cytogenetics Evaluated By Conventional Cytogenetic and Interphase Fluorescence in Situ Hybridization Analysis in Newly Diagnosed Multiple Myeloma in Mexico
Authors: Bourlon Christianne , Mutchinick Osvaldo , Vargas-Serafín Cesar , Santiago-Cano Virginia , Rivera Renata , Barrales Olga , Barrera Georgina , Jimenez Guadalupe , Martínez-Baños Deborah 
Published: October 2019

Abstract
Background
Multiple myeloma (MM) has been associated with several cytogenetic abnormalities (CA), contributing in heterogeneity of clinical outcome. CA are not always captured by conventional cytogenetic analysis (CGA), fluorescence in situ hybridization (FISH) has emerged as a useful assessment. CA that confer poor outcome include: t(4;14), t(14;16), 17p13 deletion, 13 deletion and complex karyotypes. No data regarding CA evaluated by FISH and its correlation with clinical outcome has been reported in Mexican population.
Methods
Prospective study carried between October 2006 and August 2012 in patients with newly diagnosed and untreated MM, were enrolled at our institution. Cytogenetic studies including CGA and FISH with probes for 17p13.1, 13q14.3, t(4;14), t(11;14), t(14;16), and in some cases IGH as screening test were performed. Clinical and laboratory data were collected. A high cytogenetic risk group (HCGRG) was considered for analysis which included patients with one or more of 17 deletion, 13 deletion, t(4;14), t(14;16) and complex karyotype excluding polyploidy. Continuous variables were described as medians and range, categorical variables as frequencies and proportions. Survival analysis was determined by Kaplan-Meier curves. Survival related prognostic factors were analyzed with the Cox proportional hazards regression model. Overall Survival (OS) was calculated from time of treatment initiation until death, patients that did not received therapy were excluded from the analysis. Progression-free survival (PFS) was calculated from the time of treatment initiation to the date of progression.
Results
Total of 73 patients were included. Baseline characteristics are shown in table 1. The median follow-up was 21 months (95% CI 1-70).Successful FISH was obtained in 100% of cases, CA by this method were detected in 40 patients (54.8%). CGA was useful for diagnosis in 53 cases (72.6%) with CA detected in 11 patients (20.8%). Related CA are shown in table 2. The median OS was 44 months (95% CI, 35.1-54.5) and PFS was 32.5 months (95% CI, 18.96-46.101).
In the univariate analysis the variables associated with a shorter OS were: isotype (p =0.03; 95% CI 1.031-1.843), presence of bone plasmocytoma (BP) (p=0.015; 95% CI 1.29-10.68), FISH del13q14 (p=0.004; 95% CI 1.408-8.247), FISH IGH (p=0.028; 95% CI 1.097-5.087) and HCGRG (p=0.001; 95% CI 1.77-9.47). In the multivariate analysis isotype (p=0.033; 95% CI 1.029-2.009), presence of BP (p=0.010; 95% CI 1.48-18.33), FISH del13q14 (p=0.045; 95% CI 1.024-7.19) and patients in the HCGRG (p=0.002; 95% CI 1.84-13.757), were independent prognostic factors for OS.
Variables associated with shorter PFS in the univariate analysis were: ISS (p=0.01, 95% CI 1.15-4.45), DS (p=0.01, 95% CI 1.09-2.47) and the presence of any CA (p=0.04, 95% CI 0.08-0.98). None were significant in the multivariate analysis.
Conclusions
This is the first report to show data about cytogenetics by CGA and FISH and its association with clinical outcomes in Mexico.
Our distribution of CA is similar to the previously reported, except for 13 and 17 deletions, possibly due to different techniques and cut off values.
The presence of BP and patients in HCGRG was associated to shorter OS.
PFS and OS of patients in de HCGRG differs from other reports being significantly lower. This could be explained by our lack of access to drugs that overcome the negative prognosis of some CA, this is due to financial limitations.
Our evaluation panel of CA is able to identify a group of patients with an unfavorable prognosis. It is mandatory to asses an alternative for financial protection for this group through a social program.
TABLE 1. Baseline characteristics VARIABLE CATEGORY n (%) Total of patients 73 Age (years) 62 (35-87) Gender Male 33 (45.2) Isotype IgG IgA Kappa Lambda Biclonal 35 (47.9) 22 (30.1) 6 (8.2) 7 (9.6) 3 (4.1) ECOG PS 1 2 3 4 35 (47.9) 19 (26) 10 (13.7) 9 (12.3) ISS Stage I Stage II Stage III 11 (15.1) 16 (21.9) 46 (63) Durie Salmon (DS) Stage 1A Stage 1B Stage 2A Stage 2B Stage 3A Stage 3B 6 (8.2) 0 (0) 4 (5.5) 1 (1.4) 38 (52.1) 24 (32.9) Bone Plasmocytoma (BP) 11(15.1) Extramedullary disease 4 (5.4)
TABLE 2. Cytogenetic abnormalities METHOD CATEGORY n (%) FISH 13q14 17p13 t(4;14) t(11;14) t(14;16) IGH >1 abnormality 19 (26) 16 (21.9) 8 (10.9) 5 (6.8) 6 (8.2) 26 (35.6) 11 (15) CGA del13 del17 Complex karyotype Polyploidy 4 (5.4) 3 (4.1) 8 (10.9) 7 (9.5) HCGRG 20 (27.4)

Disclosures
No relevant conflicts of interest to declare.