Risk of second primary malignancy in patients with AL amyloidosis treated with lenalidomide

To The Editor: Second primary malignancy (SPM) is a growing issue for cancer survivors [1,2]. SPM has been associated with radiation therapy, anthracyclines, alkylating agents, and topoisomerase inhibitors [3]. Recently an increased incidence of invasive SPM has been observed with lenalidomide (7.6%) compared with controls (2.9%) in patients with newly diagnosed myeloma receiving lenalidomide in combination with melphalan [4] or as long-term maintenance therapy following high-dose melphalan with autologous stem cell transplantation [5,6]. In a retrospective pooled analysis of 11 clinical trials of lenalidomide-based therapy for relapsed/refractory myeloma, the overall incidence rate (IR, events per 100 patient-years) of invasive SPM was 2.08 [7]. Lenalidomide treatment can be effective in AL amyloidosis. In 2007, our group and the Mayo Clinic described promising results of phase 2 trials [8,9]. In view of emerging data on SPM in myeloma with lenalidomide treatment, we performed a post hoc analysis for the incidence of SPM in the patients with AL amyloidosis treated with lenalidomide at Boston Medical Center. Occurrence of SPM was reported by the patient and/or referring physician and confirmed by the site by reviewing the pathology. Between 2004 and 2011, 82 patients with AL amyloidosis were treated with lenalidomide and dexamethasone (ClinicalTrials.gov: NCT00091260) [9]. The median age was 62 years (range, 40–82) and 63% were male. Seventy-eight patients (95%) had received prior therapy (94% prior melphalan-based therapy). The median duration of lenalidomide treatment was nine cycles (range, 1–69). Sixteen (20%) patients received lenalidomide treatment for > 24 months. Hematologic response was evaluated in 68 patients after completion of three cycles of therapy; patients who withdrew from the study or who had not completed at least three cycles were not evaluable for response assessment. A complete hematologic response was seen in 11 patients (16%) and a partial hematologic response was seen in 30 patients (44%), for an overall response rate of 60%. The median time to best hematologic response was 6 months. Thirty patients (44%) had a measurable organ response. The median overall survival is not yet reached with a median follow-up for 32 months (range, 3–92). Six patients were noted to develop SPM. The total follow-up was 2.46 per 100 patient-years. One patient developed primary lung cancer with metastases after 24 months of lenalidomide therapy; he was a cigarette smoker and had prior treatment with oral melphalan. Additionally, five patients developed nonmelanoma skin cancer. There were no cases of hematologic malignancy or B-cell lymphoproliferative disorder. Therefore, the IR of invasive cancer (without nonmelanoma skin cancers) was only 0.44 per 100 patient-years (95% CI, 0.05–2.88) in this trial. This compares favorably to the annual incidence of invasive cancers in the United States for the general population. Age-specific IRs of invasive cancers across all sites identified through the SEER program are 1.26 among persons aged 60–64 years; 1.74 among persons aged 65–69 years; 2.09 among persons aged 70–74 years; 2.39 among persons aged 75–79 years; 2.46 among persons aged 80–84 years; and 2.18 among persons aged 85 years [10]. In summary, lenalidomide-based treatment in AL amyloidosis did not appear to increase the IR for invasive SPM compared to the IR for invasive cancers in general population. Longer follow-up and additional patient accrual may be needed to better define the risk of SPM in this patient population.