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.

Allogeneic hematopoietic stem cell transplantation in patients with therapy‐related hematologic malignancies developing after multiple myeloma

“…Aldoss et al reported 13 patients with ALL after MM treatment (1.3% of all ALL patients) and reported a 1-year OS of 77% in this group. 19 The 2-year OS among patients with B-cell t-ALL after allogeneic HCT in our study (66.7%) is comparable to existing literature on allogeneic HCT outcomes in high-risk de novo ALL. 22 Recent studies have reported favorable outcomes of t-ALL after allogeneic HCT, however, have not separately reported outcomes or impact of allogeneic HCT in patients with a previous history of MM.…”

“…Although both B-cell ALL and MM arise from post germinal center B-lymphocytes, t-ALL arising after MM treatment was shown to be a clonally unrelated therapy-related malignancy. 19 Of note, in contrast to t-MDS/AML, there is no evidence of disease-related factors in the development of t-ALL after MM. No cases of ALL were found in a large Swedish population-based study comparing secondary malignancies in patients with MGUS compared to controls.…”

“…20 In a meta-analysis of lenalidomide maintenance, 12.5% of all hematological malignancies in lenalidomide arm were t-ALL while there were no reported cases of t-ALL in the arm which did not receive lenalidomide. 19 The exact incidence of t-ALL, other predisposing factors, duration of exposure needed are still unclear and need further research. Aldoss et al reported 13 patients with ALL after MM treatment (1.3% of all ALL patients) and reported a 1-year OS of 77% in this group.…”

Therapy-related acute lymphoblastic leukemia is a distinct entity with adverse genetic features and clinical outcomes

“…Of note, a recent study of 13 t-ALL cases by Aldoss and colleagues reported that t-ALL arising after multiple myeloma is clonally unrelated to the original malignancy. 20 Collectively, the data suggest that different pathogenic mechanisms exist for the development of t-ALL, which may be driven by inherited cancersusceptibility genes in a small subset of patients, whereas other patients develop the disease de novo as a result of genotoxic effects of prior therapies.…”

Comparative study of therapy‐related and de novo adult b‐cell acute lymphoblastic leukaemia

“…A recent study of 13 tr-ALL cases by Aldoss et al analyzed paired samples of multiple myeloma and ALL using whole-exome sequencing and reported that tr-ALL arising in this setting is clonally unrelated to the multiple myeloma, supporting the notion that it represents a therapy-related leukaemia. 13 Further research on tr-ALL in patients with antecedent multiple myeloma is warranted.…”