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

Abstract

Introduction: A 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.

Methods: We 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.

Results: Each 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).

Discussion: We 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.

Keywords: chromosomal alteration; clonal evolution; multiple myeloma; prognosis; survival.

Figure 1

(A) Time of follow-up for patients with 1 time point of aberration analysis (patients UPN01 to 04), patients with >1 time point of aberration analysis and no new clone emerging in the course of disease (patients UPN05 to 16; subgroup 1), and patients with >1 time point of aberration analysis and a new clone emerging in the course of disease (patients UPN17 to 25; subgroup 2). (B) Progression-free survival (first progression after first diagnosis) comparing subgroup 1 vs. subgroup 2. (C) Overall survival comparing subgroup 1 vs. subgroup 2. (D) Progression-free survival in relation to chromosomal alterations comparing subgroup 1 (next progression subsequent to last FISH) vs. subgroup 2 (next progression subsequent to detection of the new clone).

Figure 2

Molecular characterization of the cohort; amplifications (dark yellow), deletions (red), translocations (light blue), and rearrangements (dark green) according to FISH probes. Light colors (yellow and red) indicate likely interpretation of the observed FISH results. (A) Overview of all alterations detected. (B) Alterations characterizing the new clones observed in patients UPN17 to 25. (C) Proportion of patients with altered chromosomes: without the new clone (dark yellow), with the new clone before (light blue), and after (dark blue) detection of the new clone.

Figure 3

Differences in measured laboratory parameters. For patients in subgroup 1, laboratory parameters measured before (light blue) and after (blue/green) last FISH. For patients in subgroup 2, laboratory parameters measured before (light blue) and after (yellow) detection of the new clone. (A) κ and λ light chains measured in serum. (B) LDH activity. (C) Gradient of monoclonal protein (M-gradient).

Figure 4

Duration of therapies applied in the course of disease for patients in subgroups 1 and 2. (A) Long-term vs. short-term therapies for patients in subgroup 1 (patients UPN05 to 16). (B) Long-term vs. short-term therapies for patients in subgroup 2 (patients UPN17 to 25). (C) Therapies with the longest duration comparing subgroup 1 vs. subgroup 2. (D) Duration of therapies for subgroup 2, applied during development of the new clone. (E) Duration of the first therapy applied after development of the new clone.