Abstract
Risk factors for acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) in patients with multiple myeloma (MM) are not well understood. We have previously shown that monoclonal gammopathy of undetermined significance (MGUS) is associated with an excess risk of AML/MDS, indicating an inherent excess risk of AML/MDS in plasma cell disorders. In addition, randomized studies have shown that lenalidomide maintenance is associated with increased relative risk of AML/MDS. The excess risk of AML/MDS in lenalidomide treated patients has been found to be most prominent in patients that also receive alkylating agents. A recent randomized clinical study shows that delayed autologous transplant has the same overall survival as upfront autologous transplant with high dose melphalan at 3 years of follow-up; also emerging data shows that minimal residual disease (MRD) negativity has very similar progression free survival independent of therapy. Thus, patients treated with modern combination therapy who obtain MRD negativity might not have additional benefit from upfront autologous transplant. We were motivated to better define the role of alkylating therapy in relation to subsequent risk of secondary malignancies.
All patients diagnosed with MM from January 1, 1958 to December 31, 2011 were identified from the Swedish Cancer Registry. Information was obtained regarding all subsequent hematologic malignancies among patients in the MM cohort. Each patient with MM and a subsequent AML/MDS diagnosis (i.e., cases) was matched to another MM patient without AML/MDS for year of birth, sex, and date of MM diagnosis (i.e., control group). Detailed information on baseline characteristics at diagnosis and treatment was collected from medical records. Patients with MM and AML/MDS were also compared to MM patients that developed lymphoproliferative malignancies. Characteristics at MM diagnosis, radiation therapy, and ASCT were compared between groups with Kruskal-Wallis and Chi-square tests. Cumulative chemotherapy doses were analyzed with one way ANOVA. Post hoc analysis with Fisher´s LSD was performed.
A total of 26,627 patients were diagnosed with MM in Sweden during the study period. Of these, 224 patients developed hematological malignancies. Data was found for 89 MM and subsequent AML/MDS patients and they were matched to 89 controls. Preliminary results from the first 12 controls were available for analysis, number of controls will be updated as more data has been reviewed. A total of 100 patients had lymphoproliferative malignancies and 1/3 of them were randomly selected. The demographic and clinical characteristics for all groups are listed in Table. The median age at MM diagnosis was 67 years (39 females and 50 males) for cases, 72 years (7 females and 5 males) for controls and 70 years (10 females and 23 males) for patients with lymphoproliferative malignancies. The median time from MM diagnosis to AML/MDS diagnosis was 3.8 (range 0.4-17.1) years and 3.4 (range 0.4-29.4) years for patients who developed lymphoproliferative malignancies. The mean cumulative melphalan dose was 1,318 mg (SD ± 1,159 mg) for cases, 704 mg (SD ± 588 mg) for the controls and 967 mg (SD ± 978 mg) for patients who developed lymphoproliferative malignancies. There was a statistically significant difference of mean cumulative melphalan dose between groups (F (2,123) = 3.14, p= 0.047). Post hoc analysis confirmed that cases had a statistically significant higher mean cumulative melphalan dose compared to controls, p <0.05.
The preliminary results from this large nationwide population based study including almost 27,000 MM patients in Sweden over >50 years shows that the mean cumulative dose of melphalan was higher in MM patients who developed AML/MDS compared to MM patients who did not. With the average myeloma patient living over 10-15 years from diagnosis, strategies to avoid secondary complications is becoming more important. Our results showing that melphalan is associated with an increased risk of AML/MDS, call for studies using response driven (i.e. MRD based) therapy in myeloma; were high dose melphalan is rather offered to patients who are MRD positive.
No relevant conflicts of interest to declare.
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