Do we need cytogenetics in the follow‐up of multiple myeloma?

Abstract

Patients with multiple myeloma (MM) have a very heterogeneous outcome, with a median overall survival (OS) ranging from less than 2 years to more than 10 years. MM is characterized by chromosomal instability and chromosomal abnormalities (CAs). Interphase fluorescence in situ hybridization (FISH) on purified myeloma cells is the standard technique for the analysis of CAs. Several high-risk classifications have been proposed. The International Myeloma Working Group identified t(4;14), t(14;16), t(14;20), del(17p) and non-hyperdiploid karyotype as high-risk cytogenetics in newly diagnosed (ND)MM regardless of treatment. They recommended that t(4;14) and del(17p) should be included in routine testing (Sonneveld et al, 2016). Chromosome 1 abnormalities, particularly gain(1q), are also associated with poor prognosis. A recent report analysed patients with a “double hit”, which is defined by the co-occurrence of at least any two of the following: (i) t(4;14), t(14;16), t(14;20); (ii) del(17p); and (iii) gain(1q). Double-hit patients showed a very poor outcome and triple-hit patients had a median OS of less than 2 years (Shah et al, 2018). Most of the data on the impact of CAs on outcome came from the NDMM setting. Although no treatment appeared to be able to completely overcome the adverse prognosis of CAs, there were data supporting specific treatment choices over others. For instance, in the transplant setting, bortezomib seemed to at least partly overcome the adverse effects of t(4;14) (Avet-Loiseau et al, 2010) and del(17p) (Goldschmidt et al, 2018a), although with no significant benefit in those patients with both the abnormalities. Double autologous stem cell transplantation (ASCT) vs. single ASCT after bortezomib induction improved OS in patients with at least one high-risk CA, including del(17p) and/or t(4;14) and/or t(14;16) (Cavo et al, 2017). The association of the second-generation proteasome inhibitor carfilzomib with lenalidomide and dexamethasone as pre-transplant induction therapy induced similar rates of response and minimal residual disease (MRD) negativity both in highand standard-risk patients (Gay et al, 2018). Changes in clonal structures and CAs between diagnosis and relapse, based on clonal evolution, were reported (Weinhold et al, 2016; Oliva et al, 2018). Standard-risk patients may therefore acquire high-risk CAs, although a few data are available on this specific process. Not even in the relapse setting has any treatment completely overcome the adverse prognosis of CAs; nevertheless, evidence has suggested the potential benefits of specific therapies (Leleu et al, 2015; Avet-Loiseau et al, 2016; Weisel et al, 2017). In the present issue of the British Journal of Haematology, Cook et al (2019) reported long-term follow-up data of the randomized Myeloma X trial (ISCRTN60123120), comparing salvage ASCT vs cyclophosphamide treatment, after bortezomib-based induction at first relapse. Data on chromosomal analysis was available for about 50% of patients at trial registration and around 14% had CA data available both at diagnosis and at trial registration. Around 20% of patients with both evaluations changed cytogenetic risk group, with 12 2% of standard-risk patients at diagnosis evolving into high risk at first relapse. In other case series, FISH analysis at relapse provided new information in up to 55% of patients (Smith et al, 2015; Oliva et al, 2018). Despite the limitation of the low numbers, the analysis of changes in risk group from diagnosis to relapse is of interest. First, because these findings suggest a progressive subclonal selection, even if the exact percentage of patients still needs to be determined, and even if the risk could vary according to the administered treatment. Secondly, if we believe that it is time for a risk-adapted approach not only in the upfront, but also in the relapse setting, we cannot rely on evaluations performed at diagnosis; these should be repeated at relapse. The main open issue concerns the minimum panel that should be required in the context of the several available reports on more than one CA conferring adverse prognosis. Correspondence: Dr. Francesca Gay, Myeloma Unit, Division of Haematology, University of Torino, Azienda OspedalieroUniversitaria Citt a della Salute e della Scienza di Torino, via Genova 3, 10126 – Torino, Italy. E-mail: [email protected] editorial comment