Characteristics and Outcomes of Patients with Second Hematological Malignancies after Autologous Hematopoietic Cell Transplantation for Multiple Myeloma

Background: There is an increased risk of second primary malignancies including second hematological malignancies (SHM) in multiple myeloma (MM) patients undergoing autologous stem cell transplant (auto-SCT) followed by lenalidomide maintenance. We analyzed the characteristics and outcomes of patients who developed SHM after an auto- SCT for MM. Methods: A retrospective study of all MM patients who underwent auto- SCT at Mayo Clinic, Rochester between January 1, 1990, and 31 August 2023 and later developed SHM. Demographic, clinical and pathologic data were collected retrospectively. Overall survival (OS) was calculated from the date of auto-SCT to the date of last follow up. Statistical analyses were performed using GraphPad prism 9.0. Chi-square test was used to calculate the difference between categorical variables. Kaplan Meier method and log rank test were used to estimate OS. Results: Among 3513 patients who underwent at least 1 auto-SCT, 104 (2.9%) developed a SHM at a median follow up of 59 (range, 0.2-265) months. Patients who developed SHM, more frequently received pretransplant alkylating agents (37.5 vs 24.2 %, odds ratio [OR], 1.87; P=0.003) and topoisomerase II inhibitors (anthracyclines/etoposide) (17.3% vs 10.4%, OR [1.79]; P=0.03) compared to a control group of MM patients without SHM. Further, exposure to lenalidomide (77.8% vs 57.6%, OR[2.59]; P <0.0001) and radiation therapy (32.6% vs 23.1%, [1.54]; P=0.04) were more often seen in the SHM cohort compared to control group. Among the 381 patients who underwent > 1 auto- SCT, 3.1% developed SHM. Therapy related myeloid neoplasms (t-MN) accounted for 90.3% of cases [n=94; t-myelodysplastic syndrome (t-MDS=64), t-acute myeloid leukemia (t-AML=12), t-MDS transformed to AML(n=16), chronic myeloid leukemia (n=1), MDS/myeloproliferative neoplasm overlap syndrome (n=1)]. Eight patients (7.6%) developed therapy related B- cell acute lymphoblastic leukemia (t-ALL); Philadelphia (Ph) negative ALL (n=7) and Ph- like ALL (n=1). One patient each developed mixed phenotype acute leukemia and acute leukemia, not otherwise specified. Sixty patients (57.6%) were males and the median age at diagnosis of SHM was 70 (range, 43-84) years. The median time from auto-SCT to diagnosis of SHM was 58.5 (range, 7-236) months. In a multivariate analysis, receiving an alkylating agent (hazard ratio [95% confidence interval]: 2.51 [1.54 to 4.01]; P = 0.0002) and/or topoisomerase II inhibitor as induction for MM (3.12 [1.59 to 5.88]; P = 0.0006), exposure to lenalidomide (7.08 [3.92 to 13.50]; P = <0.0001) and radiation therapy (1.60 [1.02 to 2.44]; P = 0.03) were independent predictors of developing SHM. At diagnosis, 57% (n=37) of t-MDS and 71% (n=20) with t-AML had high risk disease per R-IPSS and 2022 European Leukemia Net respectively. Clonal abnormality in chromosome 5 and/or 7 was present in 45% (n=42) of patients. Complex and monosomal karyotype was seen in 32% (n=30) with t-MN. The most frequently mutated genes based on next generation sequencing data included TP53 (n=33), DNMT3A (n=9), RUNX1 (n=5), TET2 (n=4) and CEBPA (n=4). In the t-MDS/AML cohort, 3 patients (3.1%) underwent second auto-SCT and 9 (9.5%) received allogenic SCT (allo-SCT) for SHM. After a median follow-up of 27.2 months, the median OS from t-MDS/AML diagnosis was 8.04 months (95%CI, 6.1-11.0 months) and there was no difference in median OS for allo-SCT recipients versus nonrecipients (9.1 vs 6.8 months, P =0.19). In the t-ALL (n=8) cohort, all of them received lenalidomide based induction and five received lenalidomide maintenance. Most of the t-ALL patients had adverse risk cytogenetics [IKZF1 deletion (n=2), complex karyotype (n=2), TP53 mutation (n=1) and P2RY8-CRLF2 fusion (n=1)]. Three patients with t-ALL underwent allo-SCT and the median OS for allo-SCT recipients versus non recipients were 8.3 vs 7.9 months respectively, P=0.50. Among patients with SHM, 92.3% (n = 96) have died with SHM (72%) being the most common cause of death. MM patients who developed SHM had an inferior OS when compared to those without SHM (median OS, 75 vs 90 months, P =0.006). Conclusion: SHM following auto-SCT tends to have aggressive disease biology with poor outcomes. Short term follow up underestimates the risk of SHM and the higher incidence noted in our study may be due to longer follow up. As the OS in MM patients continues to improve, SHM remains an important challenge in improving long term outcomes.