Acute lymphoblastic leukemia as a clonally unrelated second primary malignancy after multiple myeloma

Abstract

Multiple myeloma (MM) patients have an 11-fold increased risk of developing myeloid neoplasms compared to the general population; however, acute lymphoblastic leukemia (ALL) is rarely observed. Given that both MM and the majority of ALL are of B cell origin, this raises the question of whether ALL in patients with MM arises from the same clone. We report 13 cases of B-cell ALL following therapy for MM. The interval from MM diagnosis to ALL onset was 5.4 years (range 3.3-10). The median age at the time of ALL diagnosis was 60 years (range 43-67). MM therapy included immunomodulatory agents in all patients and autologous hematopoietic cell transplantation in 10 (77%) patients preceding ALL diagnosis. ALL genetics showed a normal karyotype, TP53 mutation/deletion, and monosomy 7 or 7q deletion in 5, 3, and 2 cases, respectively. Analysis of paired samples of MM and ALL using whole exome sequencing demonstrated that the malignancies arose from different clones. Thus, ALL as a second primary malignancy following MM is not clonally related but could potentially represent a therapy-related leukemia.

Figure 1:. ALL as a second primary malignancy is clonally unrelated to preceding MM.

A) Cancer cell fraction (CCF) for clusters of SSNVs detected in MM and ALL samples from the same patient. Mutations were clustered by CCF for each pair of samples using PHYLOGIC. Clonal (navy blue) SSNVs were defined as events having ≥0.9 CCF in both samples. Subclonal (yellow) SSNVs were defined as events having <0.9 CCF in samples. Size of circles indicated the fraction of SSNVs. Mutations having ≥0.9 detection power in both samples are shown, and clusters with <3 mutations are excluded. At the top of each plot are reported the ID of the patient and the number of mutations considered in the plot. In the x axis are represented clonal (navy blue) and subclonal (yellow) mutations identified in ALL, while on the y axis are shown mutations found in MM; B) Copy number alteration in paired samples showing distinctive variations. The panel of each sample visualizes the total copy number ratio of each chromosome.