Estimating the Price of Progress

Concern that treatment of multiple myeloma puts patients at greater risk for developing a second malignancy dates back at least three decades. In 1979, the late Daniel Bergsagel and colleagues reported an increased incidence of acute leukemia among 364 myeloma patients treated with melphalan.¹ These findings remain relevant given the use of high-dose melphalan in the preparative regimen for patients with myeloma undergoing marrow ablative therapy followed by autologous stem cell rescue. With the advent of treatment regimens that include immunomodulatory drugs such as lenalidomide and proteasome inhibitory drugs such as bortezomib, survival for patients with myeloma has improved significantly over the past decade. However, results from three randomized, phase III trials showed an excess of hematologic and nonhematologic malignancies among newly diagnosed myeloma patients who received lenalidomide either in combination with melphalan or as single-agent maintenance therapy.

To further investigate the potential carcinogenic activity of lenalidomide, investigators, led by Meletios Dimopoulos of the University of Athens, analyzed pooled retrospective data from 11 clinical trials of lenalidomide-based therapy for treatment of relapsed/refractory myeloma (n=3,846). The overall incidence rate (events per 100 patients/year) of second primary malignancies (SPMs)was 3.62, including a 2.08 incidence rate for invasive hematologic and solid tumors (invasive cancers include all malignancies except non-invasive, non-melanoma skin carcinomas). Among invasive SPMs (n=52), the solid tumors were predominant (n=44), whereas hematologic malignancies were relatively uncommon (myelodysplastic syndrome [n=5], acute myeloid leukemia [n=1], B-cell lymphoma [n=2]). No cases of Hodgkin lymphoma or B-cell acute lymphocytic leukemia were observed. The authors concluded that the malignancy incidence rate for refractory/relapsed myeloma patients treated with lenalidomide was comparable to that expected for older adults according to Surveillance, Epidemiology, and End Results (SEER) data (2.1 per 100 patient-years for patients 65 or older).

In a separate analysis, the authors examined pooled data from two pivotal randomized phase III trials of treatment of relapsed or refractory myeloma (n=703) and found an overall SPM incidence rate of 3.98 (95% CI, 2.51-6.31) in patients treated with lenalidomide/dexamethasone and 1.38 (95% CI, 0.44-4.27) for patients treated with placebo/dexamethasone. The time to invasive SPM varied from one to 45 months in patients treated with lenalidomide/dexamethasone and from four to 25 months in the placebo/dexamethasone arm. Notably, the total on-study observation time was longer for patients in the lenalidomide/dexamethasone arm (467 person-years) than in the placebo/dexamethasone arm (219 person-years) because of the longer time to disease progression for patients treated with lenalidomide. The observed difference in incidence rate was attributed to the increased occurrence of non-melanoma skin carcinomas in the lenalidomide/dexamethasone arm (2.40 [confidence intervals 1.33-4.33] vs. 0.91 [confidence intervals 0.23-3.66] for the placebo/dexamethasone). The authors reported that the incidence rate of invasive SPMs was not significantly different between the treatment groups and was consistent with the expected incidence of invasive cancer in the general population 60 to 64 years of age based on SEER data.