Amplification of 1q21 Is Associated with Other High Risk Cytogenetic Abnormalities and Has No Independent Prognostic Significance in Patients Treated with Novel Agents
Authors: Kastritis Efstathios , Terpos Evangelos , Gavriatopoulou Maria , Roussou Maria , Eleutherakis-Papaiakovou Evangelos , Bakogeorgos Marios , Kalapanida Despoina , Orfanopoulos Spyros , Bampali Vasiliki , Meletiou Thaleia , Gika Dimitra , Mparmparoussi Despoina , Matsouka Charis , Dimopoulos Meletios A. 
Published: November 2019

Abstract
The presence of certain cytogenetic abnormalities on plasma cells is considered as one of the most important prognostic factors for patients with newly diagnosed symptomatic myeloma. Non-hyperdiploid metaphase karyotype, the presence of del 17p, t(4;14) define high risk myeloma and have been associated with shorter survival either in patients who are treated with or without high dose therapy or novel agents (thalidomide, lenalidomide, bortezomib). Abnormalities in chromosome 1, and especially amplification of 1q21 (amp1q21) has been associated to a high risk of relapse and short survival in some studies but this has not been extensively validated. 1q21 locus contains CKS1B gene and its overexpression has been linked to 1q21 gains and adverse prognosis. We sought to evaluate the prognostic importance of amp1q21 in unselected myeloma patients who were treated in a single center (Department of Clinical Therapeutics, National and Kapodistrian University of Athens).
The amp1q21 was evaluated using standard FISH after CD138 selection, according to EMN guidelines. The analysis included 324 patients with available cytogenetics and 26% had amp1q21. Patients with amp1q21 had more often hemoglobin <10 g/dl (60% vs 45%, p=0.019), ISS -3 disease and less often ISS-1 (49% vs 36% and 16.5% vs 27%, respectively; p=0.05), while they had borderline higher incidence of hypercalcemia (23.5% vs 15%, p=0.076). There were no significant differences in the age or gender of the patients, the presence of osteolytic bone disease, the type of heavy or light chain, the incidence of thrombocytopenia (platelet counts <130x109/L), elevated serum LDH (≥300 IU/L), amount of Bence Jones proteinuria or severe renal dysfunction (eGFR <30 ml/min/1.73 m2) among patients with or without amp1q21. There were no significant differences in the type of primary therapy that was given to patients with or without amp1q21. Frontline treatment was based on thalidomide in 27.5%, on lenalidomide in 32% and on bortezomib in 37% of patients; only 3.5% received conventional chemotherapy as primary therapy.
Regarding the association of amp1q21 with other cytogenetic abnormalities, there was a strong correlation of the simultaneous presence of del13q (by FISH) and amp1q21 (42% of patients with del13q had amp1q21 and 67% of those with amp1q21 had del13q, p<0.001). There was also an association of amp1q21 with the presence of t(4;14) (17% of patients with amp1q21 had the translocation vs 7% of patients without amp1q21, p=0.01). There was also a trend towards a higher incidence of del17p among those with amp1q21 (17% vs 10%, p=0.086). There was no significant association of amp1q21 with t(11;14) or t(14;16). Thus, 30% of those with amp1q21 had also del17p or t(4;14) (p=0.006) and, in total, 69% of our patients had neither amp1q21 or del17p or t(4;14), 21% had only amp1q21 and 9% had amp1q21 with either t(4;14) or del17p.
Median PFS for patients with amp1q21 was 19 months vs 24 months for patients without amp1q21 (p=0.03), while the median PFS was 28, 20 and 18.5 months for patients without any of the amp1q21, del17 or t(4;14), those with only amp1q21 and those with amp1q21 and either del17p or t(4;14), respectively (p=0.022). Survival at 3 years for patients with amp1q21 was 58% vs 70% for patients without amp1q21 (p=0.071). When the presence of other high risk cytogenetics was included, then patients without any of the amp1q21, del17 or t(4;14) had a 3-year OS of 73% vs 61% of those with only amp1q21 vs 51% for patients with amp1q21 and either del17p or t(4;14) (p=0.014). Post relapse, 2-year survival for patients with amp1q21 was 42% vs 58% for patients without amp1q21 (p=0.05), while in patients without any of the amp1q21, del17 or t(4;14) it was 69%, in those with only amp1q21 it was 54% and in those with amp1q21 and either del17p or t(4;14) it was 22 (p<0.001). In multivariate analysis, adjusting for ISS stage, t(4;14), del17p, elevated LDH, age and type of therapy, the presence of amp1q21 alone was not an independent high risk factor for overall survival, PFS or post relapse survival.
In conclusion, the presence of amp1q21 is found in 26% of newly diagnosed MM patients and is associated with other common cytogenetic abnormalities, including high risk cytogenetics. Our data, in unselected patients, indicate that the prognostic importance of amp1q21 is limited, when data on other high risk abnormalities are available.

Disclosures
No relevant conflicts of interest to declare.