Additional malignancies in multiple myeloma patients after first-line and maintenance treatment have been observed, questioning whether specific risks exist. Second primary malignancies have also gained attention since randomized data showed associations to newer drugs. We have conducted this large registry analysis in 744 consecutive patients and analyzed: 1) frequency and onset of additional malignancies; and 2) second primary malignancy- and myeloma-specific risks. We assessed the frequency of additional malignancies in terms of host-, myeloma- and treatment-specific characteristics. To compare these risks, we estimated cumulative incidence rates for second malignancies and myeloma with Fine and Gray regression models taking into account competing risks. Additional malignancies were found in 118 patients: prior or synchronous malignancies in 63% and subsequent in 37%. Cumulative incidence rates for second malignancies were increased in IgG-myeloma and decreased in bortezomib-treated patients (P<0.05). Cumulative incidence rates for myeloma death were increased with higher stage and age, but decreased in IgG-subtypes and due to anti-myeloma treatment (P<0.05). Cytogenetics in patients acquiring second primary malignancies were predominantly favorable, suggesting that indolent myeloma and long disease latency may allow the manifestation of additional malignancies. An assessment of the Surveillance, Epidemiology, and End Result Program of the National Cancer Institute and our data with long-term follow up of 25 years confirmed a prevalence of second malignancy of 10% at 25 years, whereas death from myeloma decreased from 90% to 83%, respectively. Our important findings widen our knowledge of second malignancies and show that they are of increasing relevance as the prognosis in myeloma improves and mortality rates decrease.
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