Chromosome 1q21 aberrations identify ultra high‐risk myeloma with prognostic and clinical implications

Abstract

Numerical abnormalities of chromosome 1q (+1q21) are common in patients with newly diagnosed multiple myeloma (MM) but their prognostic impact remains a matter of debate. In addition, the impact of the number of copies of 1q21 is not known. We analyzed 912 consecutive patients with symptomatic MM to evaluate the prognostic implications of +1q21 and of their copy number variations, as assessed by FISH. At the time of initial diagnosis, 249 (27.3%) patients had +1q21, of which 150 (16.4%) had 3 copies and 99 (10.9%) had 4 or more copies. Presence of +1q21 was associated with advanced ISS stage (p = .003), concurrent presence of other cytogenetics aberrations and advanced R‐ISS stage (p < .001). Patients with +1q21 had inferior PFS (median 34 vs. 20 months, p < .001) and OS (median 75 vs. 44 months, p < .001) but the copy number of 1q21 had no additional prognostic impact. In multivariate analysis, adjusting for R‐ISS, age, treatment and HDM, +1q21 remained an independent prognostic factor both for PFS (p < .001) and OS (p = .008). The detrimental prognostic effect of +1q21 was more profound in R‐ISS‐3 patients, identifying a subgroup with OS of just 16 months (vs. 46 for R‐ISS‐3 without +1q21, p < .001). We further validated our findings in an independent cohort of 272 patients. In conclusion, the presence of +1q21 is associated with more advanced disease, inferior PFS, and OS but especially patients with R‐ISS‐3 disease and +1q21 have a very poor outcome comprising an ultra‐high‐risk group.

Impact of 1q gains on treatment outcomes of patients with newly diagnosed multiple myeloma in a real‐world Swedish population receiving modern treatment

“…Interestingly, similar findings regarding depth of response in patients with dup(1q) were seen in another study where patients were treated with VRD. In a recently published study by Kastritis et al, 24 patients with 1q gains diagnosed between 2004 and 2021 had inferior PFS and OS regardless of the number of 1q copies as opposed to the results presented in the current study. That could partially be explained by the different time frame of the studies as well as the higher proportion of patients with 1q gains who were treated with a combination of Pi + Imids in the current study (45% compared to 30% in the study published by Kastritis et al).…”

Amp(1q) and tetraploidy are commonly acquired chromosomal abnormalities in relapsed multiple myeloma

“…The relatively high frequency of amp(1q) at relapses of up to ~45% 38 indicates a specific role for amp(1q) in disease progression. This is supported by reports showing that amp(1q) has an even more pronounced adverse impact than gain(1q) at diagnosis, 7,39 and relapse, 40 although an negative impact of amp(1q) at diagnosis was not consistently found across all cohorts 41 …”

“…This is supported by reports showing that amp(1q) has an even more pronounced adverse impact than gain(1q) at diagnosis, 7,39 and relapse, 40 although an negative impact of amp(1q) at diagnosis was not consistently found across all cohorts. 41 Several candidate genes in the commonly gained/amplified region of chromosome 1 have been implicated in drug resistance, MM cell survival, and also genomic instability. 42 In line with that, we found evidence of an antecedent amp(1q) clone in 54% of patients who developed a tetraploidy, a feature associated with genomic instability.…”

“…This is supported by reports showing that amp(1q) has an even more pronounced adverse impact than gain(1q) at diagnosis, 7 , 39 and relapse, 40 although an negative impact of amp(1q) at diagnosis was not consistently found across all cohorts. 41 …”

The prognostic significance of 1q21 gain/amplification in newly diagnosed multiple myeloma： a single‑center real world retrospective study of China

“…Mayo Clinic risk strati cation for multiple myeloma (Mayo Strati cation of Myeloma and Risk-Adapted Theray, mSMART) included 1q21, del(17p), t(4;14), t(14;16) and t (14;20) as the high-risk factors for NDMM, and it also proposed that the presence of any 2 types of high-risk factors was de ned as "double-hit" myeloma and the presence of 3 high-risk factors as "triple-hit" MM [5]. Gain or ampli cation (Gain/amp) in chromosome 1q(1q21+) is a common cytogenetic abnormality in MM, which occurs in 30-40% of patients [6][7][8]. The frequency increases from smoldering myeloma (SMM) to relapsed disease, likely to be important in disease progression [9].…”