Gain of 1q21 Does Not Predict for Immediate Progression in MGUS.

Abstract 123

In 30% to 40% of multiple myeloma tumours there is a gain of sequences at 1q21. These gains are highly associated with other poor risk cytogenetic features, a high proliferation expression index, poor prognosis and shortened post relapse survival. The abnormality has been reported to be absent or very rare in monoclonal gammopathy of undetermined significance (MGUS), suggesting that it may be a secondary event playing a role in the progression from MGUS to myeloma. Using fluorescence in situ hybridization (FISH) on purified plasma cells, we investigated gain of 1q21 using a BAC probe for CKS1B (1q21.3) in a series of 855 patients (MGUS, 88; myeloma, 767 of which 472 were treated within the context of a national trial) sent from multiple centers throughout the UK. FISH for deletion 13, IgH rearrangements, t(4;14), t(6;14), t(11;14), t(14;16), t(14;20), ploidy status, and deletions of 17p13 and CDKN2C (1p32.3) was also carried out. As expected the incidence of 1q gain was significantly lower in MGUS (20%) than in myeloma (39%) (P=0.001). In the MGUS group, all but 5 cases with the abnormality showed 3 copies of CKS1B; 2 cases showed tetrasomy, while 3 cases showed 5 copies of the gene. Apart from 2 cases where the percentage of plasma cells with the abnormality was low (21% and 26%), the MGUS patients showed the abnormality in the majority of neoplastic cells (median percentage: 87%). In myeloma cases positive for 1q gain the median percentage of affected cells was 94%; in 30% of patients there was gain of a single extra copy; 2 and 3 extra copies were found in 7% and 1% of patients, respectively; 6 cases showed amplification (≥ 6 copies). In myeloma, 1q21 gain was significantly associated with t(4;14), deletion 13, t(14;16), t(14;20) and non-hyperdiploidy (≤ 47 chromosomes) and inversely associated with t(6;14)/t(11;14). In MGUS, given the more limited number of patients, the only significant correlation was the inverted association with t(6;14)/t(11;14). Within the trial myeloma group (median follow-up of 21 mo), patients with 1q21 gain had a significant inferior overall survival compared with those with normal 1q21 copy number (33 mo vs 55 mo, P<0.001). On multivariate analysis, including other FISH genetic markers such as IgH translocations and 17p13 loss, gain of 1q21 remained an independent poor prognostic factor for overall survival (P=0.03). In order to validate the clinical role of 1q21 gain in the context of MGUS, follow-up information, calculated from the time of cytogenetic analysis, was collected for 73 of the patients with 1q results (89%). Two patients were excluded because of unrelated deaths within 2 mo of diagnosis. Fifteen patients (21%) progressed to myeloma with a median time to progression of 29 mo (range: 4 – 65 mo). Gain of 1q21 was detected in only 2 of these 15 patients (13%) compared with 13 of 56 (23%) patients who showed stable disease. The 2 patients having extra copies of 1q21 who progressed, evolved after a period of 40 and 44 mo respectively. The median follow-up of the 13 patients with 1q gain and no signs of progression was 36 mo (range: 3 – 72 mo). Therefore there was no difference in the median follow-up of the different groups. Interestingly, the 2 MGUS patients with four and five copies of CKS1B showed stable disease after 72 and 62 months, respectively; two other cases with 2 and 3 extra copies of 1q21 died 5 and 3 months from diagnosis, respectively, from myeloma-unrelated causes. The 2 MGUS patients with 1q gain who progressed to myeloma were found to be positive for other chromosomal aberrations: one carried a t(4;14) in the context of a hyperdiploid karyotype; the other showed deletions of 4p16, 5p15 and 14q32 and a hypodiploid karyotype. Thus, both cases had other abnormalities associated with a dismal prognosis in myeloma. However, within the MGUS group with 1q gain and stable disease, there were patients positive for similar abnormalities such as t(14;16), hypodiploidy, deletion 13, deletions of chromosome 16q which are similarly associated with a poorer prognosis. This multi-center study clearly shows that although gain of 1q21 results in short overall survival in myeloma, in MGUS the presence of the abnormality does not lead to rapid progression. No difference in specific associations of 1q21 gain and other genetic markers we tested was found between MGUS and myeloma that obviously explains the different contribution of the abnormality in the two conditions.