Cumulative exposure to melphalan chemotherapy and subsequent risk of developing acute myeloid leukemia and myelodysplastic syndromes in patients with multiple myeloma

Abstract

Objectives The aim of this study was to determine risk factors for development of acute myeloid leukemia/myelodysplastic syndromes (AML/MDS) in patients with multiple myeloma (MM). Methods We identified all patients diagnosed with MM in Sweden from January 1st, 1958 to December 31, 2011. A total of 26 627 patients were diagnosed with MM with during the study period. Of these, 124 patients (0.5%) developed subsequent AML/MDS. For each patient with MM and a subsequent AML/MDS diagnosis, we randomly selected a matched (age, sex, and date of MM diagnosis) MM patient without a subsequent second malignancy diagnosis. Results The cumulative melphalan exposure was significantly higher (OR = 2.8, 95% CI 1.7‐5.2; P < .001) among cases (median 988 mg; IQR 644‐1640) compared with controls (median 578 mg; IQR 360‐967). Median time to AML/MDS development was 3.8 years (IQR 2.8‐5.8). Risk of AML/MDS was not statistically altered by M protein isotype, anemia, renal failure, hypercalcemia, lytic bone lesions, or radiation therapy. Conclusion In this nationwide population‐based study, we show that increased cumulative doses of alkylating therapy with melphalan increases the subsequent risk of developing AML/MDS in patients with MM. Given improved survival in MM patients over the last decade future studies will be important to better define long‐term risks.

Increased mortality risk in multiple-myeloma patients with subsequent malignancies: a population-based study in the Netherlands

“…With each increment of calendar period, used as a surrogate for the evolution of MM therapy, we observed an overall increase of SPMs, particularly squamous-cell carcinomas of the skin, MDS, and AML. This is in accordance with findings from clinical trials [ 1 , 4 ], retrospective (population-based) studies [ 9 – 11 ], as well as with data discussed in a recently published review [ 8 ]. A potential mechanism may lie in the cumulative exposure to mutagenic anti-MM agents (e.g., alkylating drugs), thereby increasing the risk of subsequent MDS/AML development [ 11 , 12 ].…”

“…This is in accordance with findings from clinical trials [ 1 , 4 ], retrospective (population-based) studies [ 9 – 11 ], as well as with data discussed in a recently published review [ 8 ]. A potential mechanism may lie in the cumulative exposure to mutagenic anti-MM agents (e.g., alkylating drugs), thereby increasing the risk of subsequent MDS/AML development [ 11 , 12 ]. Indeed, high-dose melphalan exposure in MM patients increases mutational burden following the end of first-line treatment, until relapse by approximately 10–20% [ 13 ].…”

Clinical application of flow cytometry in patients with unexplained cytopenia and suspected myelodysplastic syndrome: A report of the European LeukemiaNet International MDS‐Flow Cytometry Working Group

“…Occasional patients have dual diagnoses of MDS and another clonal hematological malignancy. In other cases, MDS has emerged after treatment of a preceding hematological malignancy and is therapy related MDS with or without residuum or relapse of the original disease (Jonsdottir et al, 2021). Rarely, MDS may be associated with clonal or non-clonal proliferations of NK or T-NK cells.…”

Therapy-related MDS dissected based on primary disease and treatment—a nationwide perspective

“…Other non-myeloid hematological malignancies such as lymphoma and myeloma were also highly overrepresented in MDS patients. These malignancies are often treated with high doses of chemotherapy, which might lead to higher risk of t-MDS than other malignancies [29][30][31]. Autologous hematopoietic cell transplantation is used to treat both lymphomas and myeloma and is known to be associated with the development of t-MDS [32].…”