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The Relative Risk of Prognostic Factors of Age Stratified Multiple Myeloma

Background: Age is a pivotal prognostic factor for multiple myeloma (MM). The risk of evolving from MGUS and SMM to symptomatic MM steadily increases with age. And there are nuances in clinical manifestations and cytogenetic characteristics between young and old patients. The aim of this study is to delineate the clinical and laboratory features and determine the relative contribution of ISS, performance status and cytogenetic abnormalities in each age MM patients.
 Methods: In this study, 778 MM patients were enrolled in the prospective, non-randomized BDH2008/02 clinical trial between January, 2008 and December, 2016. Briefly, the patients accepted bortezomib or thalidomide-based induction therapy. Transplantation eligible patients accepted ASCT, otherwise they accepted the original regimen consolidation therapy. Subsequently, unless intolerance, patients received either thalidomide-based or lenalidomide-based maintenance therapy for two years. Conventional FISH panel included del(13q), del(17p), gain(1q), t(11;14), t(4;14), t(14;16), and t(14;20). The positive cut-off value for chromosome deletion or gain was 20%, and for chromosome translocation was 10%. A multivariate Cox proportional-hazards model was developed to assess the variables with significant effects on PFS and OS. Explained variation of variables was quantified by RD2. Statistical analysis was conducted by Stata/MP 16.0 (Stata Corp., TX, USA) and SPSS 26.0 (IBM Corp., Chicago, Illinois, USA).
 Results: Among 778 patients with complete data, 59.5% (463/778) were younger than 60 years old, 31.4% (244/778) were 61-70 years old, and only 9.1% (71/778) were over 71 years old. The median PFS of patients≤60, 61-70 and ≥71 years of age was 36.3, 32.6 and 23.1 months, respectively (P<0.001). The median OS in each age group was 86.2, 60.7 and 34.9 months, respectively (P<0.001) (Figure A-D). The median evaluated glomerular filtration rate of the three groups was 89.1, 74.0 and 66.4 ml/min (P<0.001), respectively. The serum β2-microglobulin level gradually increased with age (P<0.001), along with the proportion of patients with ISS 3 stage. Patients ≥71 years old had a higher proportion of ECOG performance status score 3-4, twice than that of patients ≤60 years old. The incidence of high-risk IgH translocation decreased with age, and was 25.4%, 21.3% and 14.3% across age groups. The incidence of gain(1q) increased with age, and was 43.9%, 47.1% and 54.8%, respectively. The incidence of del(17p) and del(13q) seldom changed with age (Figure E). With age, the risk of high-risk cytogenetic abnormalities did not change significantly, accounting for about 50% in each age group. The risk of ISS gradually decreased, accounting for 36%, 27%, and 14% in ≤60, 61-70 and ≥71 year subgroups, respectively. The risk of the ECOG performance status gradually increased with age, accounting for 10%, 17%, and 36% in the three subgroups (Figure F). The overall response rate of induction treatment gradually decreased with age, and were 90.2%, 81.9%, and 69.2%, respectively (P<0.001). Elderly patients with impaired renal function or more than one high-risk cytogenetic abnormalities might benefit more from bortezomib based treatment than younger patients (Figure G).
 Conclusion: Age is an important prognostic factor in MM. With age, the risk of MM progression or death steadily grows. Cytogenetic abnormalities are equally important in every age group. The risk of poor performance status increases in elderly patients with a reduction risk in ISS. Elderly patients should focus on the status of frailty and molecular events to determine treatment.
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 No relevant conflicts of interest to declare.
