Background: Novel agents have changed the treatment landscape of multiple myeloma (MM). The improvement in treatment outcomes of MM patients is associated with an increased risk of developing a second primary malignancy (SPM).

Aim: To describe SPMs in patients with MM treated at the Department of Hematology in Cagliari between 2004 and 2025.

Methods: We analyzed the patients with symptomatic MM diagnosed between 01 January 2004 and 01 July 2025. Patients with a previous malignancy were excluded. Patients had to have received at least one treatment for MM during the follow-up period, either with new agents alone, with chemotherapy plus new agents or with chemotherapy alone. Patients were followed for the occurrence of SPMs in the cancer registry from the date of diagnosis until death, the occurrence of the first SPM, or July 01, 2025, whichever occurred first. Statistical analysis was performed using R packages.

Results: There were 469 eligible patients included in the cohort analysis. Forty-two (8.9%) patients developed at least 1 SPM, of which 64.3% developed solid tumors and 35.7% developed hematologic malignancies. 52.4% were men and the mean age at the time of SPM diagnosis was 71 years (41-89). The hematologic malignancies were represented by Hodgkin lymphoma (2.4%), acute myeloid leukemia (9.5%), myelodysplastic syndromes (21.4%), follicular non-Hodgkin lymphoma (2.4%) and solid cancers were found in the colorectal tract (14,2%), breast (12%), prostate (12.6%), ovary (4.7%), parathyroid glands (4.7%), brain (glioblastoma) (2.4%), lung (2.4%), kidney (4.7%), thyroid (papillary carcinoma) (2.4%); bladder (4.7%) and uterus (4.7%). The median time between MM and SPM diagnosis was 53 months (6-317). 62% of patients were treated continuously with lenalidomide and 55% received autologous stem cell transplantation (ASCT) (52% with tandem ASCT). 31 (74%) patients developed SPM during the first line of therapy. Death occurred in 43% of patients, 88% of which due to SPMs. Only 45% of patients continued MM treatment. There was a statistical difference in overall survival from the diagnosis of SPMs between the population affected by hematologic and solid cancers (p = 0.0174). However, there was no difference in relation to lenalidomide exposure (p = 0.692) and ASCT treatment (p = 0.235).

Conclusion: The development of SMPs represent and issue in the treatment of MM with modern therapies. In particular, hematologic cancers appear to have a greater impact on overall survival than solid tumors and deserve special management by the myeloma team.

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2025
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