Second Primary Malignancy Among Patients with Plasma Cell Myeloma Receiving First-Line Lenalidomide-Based Therapy: A Population-Based Analysis

Introduction: Clinical trials have suggested that patients with plasma cell myeloma treated with lenalidomide may have an increased risk of second primary malignancies (SPM; Dimopoulos MA, et al., Blood. 2012). Whether such risks are of significant relevance in real-world clinical practice, particularly among older patients, remains to be investigated, as evidence thus far has been limited to few retrospective series.

Methods: Using the linked SEER-Medicare database covering 35% of the US population (with successful linkage of >95% individuals aged 65 or over), we identified Medicare beneficiaries with plasma cell myeloma diagnosed in2007-2015, who received first-line anti-myeloma therapy. We limited our cohort to patients with complete records of outpatient prescriptions since diagnosis (including beneficiaries covered by fee-for-service [FFS]or health maintenance organization [HMO]Medicare plans), and who received at least one oral anti-myeloma agent (including steroids) within 90 days of diagnosis. We defined first-line lenalidomide-containing therapy as use of lenalidomide within 90 days of diagnosis. SPM was defined as a malignancy reported to a cancer registry >90 days after myeloma diagnosis and was classified as solid tumor or hematologic. We computed cumulative incidence function (CIF) of SPM (with death being a competing event) and compared SPM rates between patients treated with or without first-line lenalidomide using Fine-Gray's model, adjusting for age at diagnosis, sex, race and ethnicity, presence of a cancers before myeloma diagnosis, and plasmacytoma vs myeloma histology. All estimates are provided with 95% confidence intervals (CI).

Results: The analysis included 9,850 Medicare beneficiaries starting their first-line therapy. Median age was 75 years [yr], 52% were men, 67% were white non-Hispanic, 21% had a previous malignancy, and 3% had a histologic designation of plasmacytoma. First-line lenalidomide was prescribed to 4,009 (41%) patients. Patients receiving lenalidomide were on average younger (median age, 74 vs 76 years [yr]; P <.001), and more likely to be white non-Hispanic (69 vs 66%; P=.002).

During median follow up of 5.0 years, 423 patients (4.3%) developed SPM, including 361 solid tumors (85%) and 61 hematologic malignancies (14%). The most common SPM histology included cancer of the lung/bronchus (11%), colorectal cancer (11%), melanoma (10%), acute myeloid leukemia or myelodysplastic syndrome (9%) and prostate cancer (7%). The cumulative incidence of any SPM at 5 yr was 5.3% (95%CI, 4.5-6.1%) for patients who received first-line lenalidomide, and 4.4% (95%CI, 3.9-5.0%) for those who did not (Fig. 1A). The 5 yr cumulative incidences for solid tumor SPMs were 4.7% (95%CI, 3.9-5.5%) with and 3.6% (95%CI, 3.1-4.2%) without lenalidomide exposure (Fig. 1B). The 5 yr cumulative incidences for hematologic SPMs were 0.6% (95%CI, 0.4-1.0%) with and 0.8% (95%CI, 0.6-1.1%) without lenalidomide exposure (Fig. 1C).

In a multivariable competing-risk model, the use of first-line lenalidomide was not associated with a significantly increased risk of SPM (sub-hazard ratio [SHR], 1.06; 95%CI, 0.88-1.29; P=.53). Furthermore, the use of lenalidomide was not associated with increased risk of solid tumor SPM (SHR, 1.13; 95%CI 0.92-1.40; P=.24), or of a hematologic malignancy (SHR, 0.72; 95%CI 0.42-1.23; P=.23). In a sensitivity analysis, the rate of SPM was not significantly different between FFS vs HMO plan enrollees (5 yr CIF 4.7% vs 4.9%; SHR, 1.05; 95%CI 0.86-1.27; P=.65).

Conclusions: In this large, population-based study, use of first-line lenalidomide therapy among older patients with myeloma was not associated with a statistically significantly increased risk of any SPM, either solid tumors or hematologic cancers. Additional factors such as dose and duration of lenalidomide therapy or concurrent use of alkylating agents may drive the risk of SPM in patients treated with lenalidomide and should be investigated in future studies.

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