The Role of Clonal Evolution on Progression, Blood Parameters, and Response to Therapy in Multiple Myeloma

IntroductionA variety of biomarkers are considered for diagnosis (e.g., β2-microgobulin, albumin, or LDH) and prognosis [e.g., cytogenetic aberrations detected by fluorescence in situ hybridization (FISH)] of multiple myeloma (MM). More recently, clonal evolution has been established as key. Little is known on the clinical implications of clonal evolution.MethodsWe performed in-depth analyses of 25 patients with newly diagnosed MM with respect to detailed clinical information analyzing blood samples collected at several time points during follow-up (median follow-up: 3.26 years since first diagnosis). We split our cohort into two subgroups: with and without new FISH clones developing in the course of disease.ResultsEach subgroup showed a characteristic chromosomal profile. Forty-three percent of patients had evidence of appearing new clones. The patients with new clones showed an increased number of translocations affecting chromosomes 14 (78% vs. 33%; p = 0.0805) and 11, and alterations in chromosome 4 (amplifications and translocations). New clones, on the contrary, were characterized by alterations affecting chromosome 17. Subsequent to the development of the new clone, 6 out of 9 patients experienced disease progression compared to 3 out of 12 for patients without new clones. Duration of the therapy applied for the longest time was significantly shorter within the group of patients developing new clones (median: 273 vs. 406.5 days; p = 0.0465).DiscussionWe demonstrated that the development of new clones, carrying large-scale alterations, was associated with inferior disease course and shorter response to therapy, possibly affecting progression-free survival and overall survival as well. Further studies evaluating larger cohorts are necessary for the validation of our results

Chromosomal Abnormalities and Prognosis in NPM1-Mutated Acute Myeloid Leukemia : A Pooled Analysis of Individual Patient Data From Nine International Cohorts

PURPOSE: Nucleophosmin 1 (NPM1) mutations are associated with a favorable prognosis in acute myeloid leukemia (AML) when an internal tandem duplication (ITD) in the fms-related tyrosine kinase 3 gene (FLT3) is absent (FLT3-ITDneg) or present with a low allelic ratio (FLT3-ITDlow). The 2017 European LeukemiaNet guidelines assume this is true regardless of accompanying cytogenetic abnormalities. We investigated the validity of this assumption. METHODS: We analyzed associations between karyotype and outcome in intensively treated patients with NPM1mut/FLT3-ITDneg/low AML who were prospectively enrolled in registry databases from nine international study groups or treatment centers. RESULTS: Among 2,426 patients with NPM1mut/FLT3-ITDneg/low AML, 2,000 (82.4%) had a normal and 426 (17.6%) had an abnormal karyotype, including 329 patients (13.6%) with intermediate and 83 patients (3.4%) with adverse-risk chromosomal abnormalities. In patients with NPM1mut/FLT3-ITDneg/low AML, adverse cytogenetics were associated with lower complete remission rates (87.7%, 86.0%, and 66.3% for normal, aberrant intermediate, and adverse karyotype, respectively; P < .001), inferior 5-year overall (52.4%, 44.8%, 19.5%, respectively; P < .001) and event-free survival (40.6%, 36.0%, 18.1%, respectively; P < .001), and a higher 5-year cumulative incidence of relapse (43.6%, 44.2%, 51.9%, respectively; P = .0012). These associations remained in multivariable mixed-effects regression analyses adjusted for known clinicopathologic risk factors (P < .001 for all end points). In patients with adverse-risk chromosomal aberrations, we found no significant influence of the NPM1 mutational status on outcome. CONCLUSION: Karyotype abnormalities are significantly associated with outcome in NPM1mut/FLT3-ITDneg/low AML. When adverse-risk cytogenetics are present, patients with NPM1mut share the same unfavorable prognosis as patients with NPM1 wild type and should be classified and treated accordingly. Thus, cytogenetic risk predominates over molecular risk in NPM1mut/FLT3-ITDneg/low AML