Treatment patterns and clinical outcomes in high‐risk newly diagnosed multiple myeloma patients carrying the 17p deletion: An observational multi‐center retrospective study

Abstract

Del17p is a genomic imbalance occurring in ∼7%-10% of myeloma at diagnosis newly diagnosed myeloma patients (NDMM) and comprises a poor prognostic factor. The goal of this study is to analyze real world data and outcomes among NDMM patients carrying 17p deletion. We report an observational, retrospective, multicenter study. Sixty consecutive patients diagnosed with multiple myeloma in the 8 participating centers diagnosed between 1/2008 and 1/2016 proven to carry 17p deletion by means of fluorescence in situ hybridization (FISH) were identified. Most received a bortezomib-based induction, over half underwent autologous hematopoietic cell transplantation (HCT); 30% of the patients gained early access to new novel agents via clinical trials, access programs or private insurance. Overall response rate (ORR) after induction was 85%; 94% for transplant eligible (TE); and 75% for transplant ineligible (NTE), and declined in subsequent treatment lines, 64% achieved ≥ VGPR. Median overall survival (OS) was 43 months; median progression free survival (PFS) was 11 months, 19 months for TE and 7 for NTE. In multivariate analysis: higher M-Spike, presence of extramedullary disease, and >50% of cells baring del17p were associated with adverse PFS; Autologous HCT and higher hemoglobin were associated with longer PFS; OS was 59 months for patients with early access to newer agents. Older age and higher M-Spike levels were associated with adverse OS, Autologous HCT was associated with favorable OS, 59.7 vs 28.7 months for NTE patients. Despite the improvement achieved with autologous HCT and new novel agents, the prognosis of patients with 17p deletion is still inferior, emphasizing the need for novel approaches.

Expression of p53 protein isoforms predicts survival in patients with multiple myeloma

“…Although del(17p) has been routinely examined in the clinical setting for many years and TP53 mutations are considered in present‐day genetic studies, the p53 landscape covers a far wider range of phenomena than just TP53 deletions and mutations 3,4 . Therefore, the study of other deregulations of the p53 pathway, particularly those that trigger defective p53 activity, are also important 3–6 …”

“…3,4 Therefore, the study of other deregulations of the p53 pathway, particularly those that trigger defective p53 activity, are also important. [3][4][5][6] The discovery of an alternative promoter in the TP53 gene in 2005 led to the identification and characterization of p53 isoforms. 7 This finding has had a profound impact on our perspective on the p53 pathway and the ways of researching p53 tumor suppressor activity.…”

High subclonal fraction of 17p deletion is associated with poor prognosis in multiple myeloma

“…[3][4][5] Currently, the minimum percentage of del17p cancer clonal fraction (CCF) indicative of poor prognosis is not known, with most studies reporting arbitrary threshold levels ranging from a single FISH 1 cell to exceeding 60% FISH 1 MM cells. [6][7][8][9] The lack of uniform analytical methods for cytogenetic assessment of del17p by FISH adds to discordant claims about CCF threshold for poor prognosis. 4,6,8,9 Genetic defects in 17p are complex and include either a deletion only or a mutation only in 1 allele of the TP53 gene or both (biallelic inactivation).…”

Assessment of TP53 lesions for p53 system functionality and drug resistance in multiple myeloma using an isogenic cell line model

“…Although MM with TP53 lesions appears to be per se responsive to therapies with novel agents 15–17 , the acquisition of additional oncogenic driver events, often in combination with outgrowth of a TP53 double-hit clone, appears to underlie the fast progress into intractable and fatal disease 18 . However, little is known about whether and to what extent the different types and constellations of TP53 lesions, i.e.…”