The prognostic value of additional copies of 1q21 in multiple myeloma depends on the primary genetic event

Abstract

Hyperdiploidy (HRD) and specific immunoglobulin heavy locus (IGH) translocations are primary chromosomal abnormalities (CA) in multiple myeloma (MM). In this retrospective study of 794 MM patients we aimed to investigate clinical features and common CA including gain(1q) in separate subgroups defined by primary CA. In the entire group, we confirmed that gain(1q) was associated with short time to next treatment and adverse overall survival (OS). The impact was worse for four or more copies of 1q21 as compared to three copies. However, in a subgroup of patients with clonal gain(11q) and without known primary IGH translocations (CG11q), already three copies of 1q21 were associated with a poor outcome; in the absence of gain(1q), patients in this subgroup had a remarkably long median OS of more than nine years. These cases were associated with HRD, coexpression of CD56 and CD117, male gender, and IgG subtype. In non-CG11q patients, four or more copies of 1q21 (but not three copies) had a significant adverse impact on outcome. Several associations with CA and clinical findings were observed for the defined subgroups. As an example, we found a predominance of early tetraploidy, plasma cell leukemia, and female gender in the t(14;16) subgroup. Our results underscore the importance of subgrouping in MM. 1 | INTRODUCTION Although novel drugs have improved the management of multiple myeloma (MM), the disease is still characterized by a marked clinical heterogeneity as reflected by overall survival (OS), ranging from less than two years to more than ten years. 1 Various factors such as patient fitness, therapy, microenvironment, and properties of the cancer itself including chromosomal abnormalities (CA) explain, at least in part, this heterogeneity. 2-5 With CA, MM can be broadly divided into two groups: about half of the cases with primary immunoglobulin heavy locus (IGH) translocations and the remaining with hyperdiploidy (HRD), the gain of odd-number chromosomes. 6 Both IGH translocations and HRD are considered primary genetic events, and as such they are mutually exclusive and present already in asymptomatic precursor stages and in the main clone. 7 These initiating events are followed by secondary events that eventually contribute to tumor progression and relapse. 8 In recent years, high-throughput technologies such as gene expression profiling (GEP) and next-generation sequencing (NGS) have been used to characterize myelomas in more detail in order to improve our understanding of myelomagenesis. 9

Gain/Amplification of Chromosome Arm 1q21 in Multiple Myeloma

“…1q21+ can be divided into 2 categories according to the increased levels of the copy number of 1q21 [ 23 , 25 , 28 , 29 , 30 , 31 , 63 , 64 ]. In studies using interphase FISH for 1q21+ detection, the patients are usually defined as those having amplification of 1q21 (amp(1q21)) when ≥10% (or 20%) of MM cells harbor at least 4 copies of 1q21, and the remaining patients with 1q21+ are defined as those having gain of 1q21 (gain(1q21)), however, a uniform definition for amp(1q21) is absent.…”

“…In a study by Schmidt et al, with 201 NDMM patients who were uniformly treated with VRd induction, among the patients lacking adverse cytogenetics (including t(4;14), t(14;16), and del(17p)) patients with gain(1q21) showed similar PFS and OS as patients with 2 copies of 1q21, while patients with amp(1q21) showed worse prognosis than those with 2 or 3 copies of 1q21 [ 30 ]. More recently, in a study by Locher et al with 794 NDMM patients [ 64 ], in which >95% were treated with an induction of PIs and/or IMiDs and 44% underwent a front-line ASCT, among patients with clonal gain of chromosome 11 and without any primary IGH translocations, patients lacking 1q21+ showed a markedly long median OS of more than 9 years. This subgroup is likely to correspond to patients with hyperdiploidy lacking 1q21+.…”

Selinexor, bortezomib, and dexamethasone versus bortezomib and dexamethasone in previously treated multiple myeloma: Outcomes by cytogenetic risk

“…28 Here, we focused our analyses on the more conservative definition of ≥4 copies of 1q21 as high risk. 29 Of particular note, overall rates of PN on DVd were 49% and 55% in standard-and high-risk patients, respectively, substantially higher than the rates on the Vd arm in that study. 27 In OPTIMISMM, patients with relapsed or refractory MM who had received 1-3 previous regimens (including two or more cycles of lenalidomide) and had progressive disease were randomly assigned 1:1 to pomalidomide, twice weekly bortezomib, and dexamethasone (PVd) or Vd.…”

“… 28 Here, we focused our analyses on the more conservative definition of ≥4 copies of 1q21 as high risk. 29 Of particular note, overall rates of PN on DVd were 49% and 55% in standard‐ and high‐risk patients, respectively, substantially higher than the rates on the Vd arm in that study. 27 …”

How to Treat High-Risk Myeloma at Diagnosis and Relapse

“…4 Other groups have also looked at amp(1q) compared with gain(1q) and found no additional prognostic effect. 18,19 When possible, sequencing panels should be used to detect subtleties in genetic variables to better identify and define a more homogenous high-risk population.…”