Cytogenetic heterogeneity has prognostic significance in NDMM

Multiple Myeloma (MM) is a heterogeneous disease with complex genetics. Many studies have now set their focus on unraveling the genetic complexity of MM with the aim to understand treatment resistance. Despite the significant improvement in outcome for MM patients through the use of novel agents, treatment can be selective for specific clones that are present when the MM patient is first diagnosed.

Maximilian Merz from Medizinische Klinik, University Hospital of Heidelberg, Heidelberg, Germany, along with his colleagues, investigated subclonal cytogenetic aberrations (CA) with the use of interphase fluorescence in situ hybridization (iFISH),  in Newly Diagnosed (ND) MM patients (pts).The prognostic significance in pts with or without bortezomib treatment and tandem ASCT was also studied, within the German part of the prospective Haemato Oncology Foundation for Adults in the Netherlands (HOVON)–65/German-Speaking Myeloma Multicenter Group (GMMG)–HD4 trial. GMMG pts were randomly assigned to either arm A: 3 cycles of vincristine, adriamycin, and dexamethasone followed by tandem ASCT and thalidomide maintenance therapy for 2 years or arm B: 3 cycles of bortezomib, adriamycin, dexamethasone (PAD), followed by tandem ASCT and bortezomib maintenance therapy for two years. The study was published in the January 2018 edition of Blood Advances.

Key findings:

• Patients (pts) = 833 were enrolled in the prospective HOVON-65/GMMG-HD4 trial
• Pts with subclones had more frequently a hyperdiploid (HD; 24.8%) or a high-risk main clone (31.0%) than patients (pts) with a t(11;14) in the main clone (10.1%)

Table 1. The frequencies of subclonal aberrations detected in the studied cohort

 

• Gains/deletions of the MYC locus are more frequently identified as a subclone (8.1%/20.5%) rather than main clone (6.2%/3.9%)
• There was a higher frequency of clonal gains of MYC in pts with other high-risk CA in the main clone (14.1%) compared to pts with HD or t(11;14) in the main clone (< 3%; P = 0.0023)
• Gains of odd-numbered chromosomes were the second most frequently found aberrations on a subclonal level (e.g. 5, 9 and 15 are associated with a HD karyotype, in 9.1%–15.4% of pts)
• IgH translocations (t(4;14), t(11;14), t(14;16)) were defined predominantly as main clone aberrations and only in 1% of pts on a subclonal level
• Other high-risk CA occurred predominantly as a main clone (gain 1q21: 23.3%/del17p: 8.0%) than a subclone (gain 1q21: 9.3%/del17p: 2.6%)
• Higher rates of very good partial remission (VGPR) or better after induction therapy and ASCT were found in pts without subclones (27.8% and 47.2%) compared to pts with subclones (19.9% and 41.1%, respectively) although this was not statistically significant
• High-risk CA were associated with adverse outcomes (whether main or subclone)
• Shorter OS observed when gains or deletions of MYC are present as a main clone and for pts with subclonal CA
• Bortezomib completely overcame the negative prognostic impact of a high-risk main clone without a subclonal CA, and abrogated with the presence of additional subclonal CA, regardless of their types (high-risk or neutral chromosomes)
• The presence of subclones was found to be an independent factor for negative outcome in pts treated with bortezomib, especially in patients with a high-risk main clone (multivariable Cox regression analysis)

This study demonstrated, for the first time, the association of clonal heterogeneity with a poor outcome. It also showed that clonal heterogeneity is a common phenomenon in MM. A higher frequency of gains and deletions of MYC on a subclonal level were also found, although they were only associated with adverse outcomes when present as a main clone. High-risk patients who do not display any subclones were found to benefit from continuous bortezomib treatment. However, it must be noted that without whole-genome data, the true number of subclones could be underestimated. Future studies will include investigating the subclones on a mutational level in order to elucidate mechanisms that lead to the observed.