Results from the Myeloma XI trial presented at the 2016 ASH Annual Meeting supported the use of lenalidomide as maintenance therapy for patients with newly diagnosed, symptomatic multiple myeloma (MM), as it extended progression-free survival without significant toxicity increases. However, in a new analysis from the trial, published in the Blood Cancer Journal, John R. Jones, MD, from the Institute of Cancer Research and the Royal Marsden National Health Service Foundation Trust in London, United Kingdom, and co-authors found that patients receiving lenalidomide maintenance had a significantly higher risk of developing secondary primary malignancies (SPM), compared with patients in the observation arm of the study (p=0.011). The association was even stronger for older patients.
The randomized, multicenter, open-label, phase III Myeloma XI study involved 2,732 patients and compared thalidomide, lenalidomide, and bortezomib induction combinations, followed by lenalidomide with or without vorinostat as maintenance therapy. 1,509 patients were transplant-eligible (median age = 61 years; range = 28-75 years) and 1,223 were transplant-ineligible (median age = 74 years; range = 51-89 years).
Patients were randomized 1:1 to receive induction with a combination regiment of cyclophosphamide and dexamethasone, with either thalidomide or lenalidomide, and dexamethasone. A total of 1,362 patients were then randomized to receive maintenance therapy with single-agent lenalidomide (n=527), lenalidomide plus vorinostat (n=305), or observation only (n=530).
Over a median follow-up of 34.3 months in the lenalidomide group and 24.2 months in the observation group, 104 SPMs in 96 patients were observed: 40 SPMs in 35 transplant-eligible patients and 64 SPMs in 61 transplant-ineligible patients.
Thirteen of the SPMs were hematologic (0.48% incidence rate), including: six cases of myelodysplastic syndromes, three cases of acute myeloid leukemia, two cases of non-Hodgkin lymphoma, one case of Hodgkin lymphoma, and one case of chronic myeloid leukemia. Of the remaining cases, 55 were solid tumors and 36 were non-melanoma skin cancer.
The cumulative incidence of SPM was 0.7 percent (95% CI 0.4-1.0) at one year, increasing to 2.3 percent (95% CI 1.6-2.7) at two years. Overall SPM incidence was highest at three years, at 3.8 percent (95% CI 2.9-4.6), and SPMs were observed more frequently in transplant-ineligible patients (5.2% vs. 2.7%).
Among patients exposed to lenalidomide at any time, the researchers observed 73 SPMs. Patients on lenalidomide maintenance had a significantly higher three-year SPM incidence, compared with patients in the observation-only cohort: 8.9 percent versus 4.0 percent (p=0.011), for a hazard ratio of 2.46 (95% CI 1.16-5.21; p=0.183).
Advanced age was the risk factor associated with the highest SPM incidence. Transplant-ineligible patients >74 years who received lenalidomide maintenance had a three-year cumulative incidence of 17.3 percent (95% CI 8.2-26.4), compared with 6.5 percent (95% CI 0.2-12.9) in the observation-only cohort (p=0.072). Comparatively, the SPM cumulative incidence for transplant-ineligible patients ≤74 years was 9.7 percent (95% CI 4.3-15.1) in the lenalidomide-maintenance group and 6.1 percent (95% CI 1.2-11) in the observation-only group (p=0.129).
During study follow-up, 38 patients (39.6%) died, 19 (50%) of whom had undergone maintenance therapy with lenalidomide (n=15). “The PFS benefit observed in patients receiving maintenance lenalidomide outweighs the SPM risk with overall trial mortality, as a consequence of SPM being only 1 percent,” Dr. Jones told ASH Clinical News. “Patients should be informed of the higher incidence of SPM with lenalidomide maintenance, compared with observation, but be reassured that more than one-third of all confirmed second malignancies are noninvasive, low-risk skin cancers and no increased incidence of second hematologic malignancies was observed.”
Noting some limitations of the study, Dr. Jones said that “this is an interim analysis, therefore the long-term SPM incidence will need to be monitored and will be reported in due course.” In addition, the trial protocol required patients on lenalidomide to be reviewed more frequently than observation-only patients, and “ reduced clinic time may result in underreporting by patients.”
Jones JR, Cairns DA, Gregory WM, et al. Second malignancies in the context of lenalidomide treatment: an analysis of 2732 myeloma patients enrolled to the Myeloma XI trial. Blood Cancer J. 2016 December 9. [Epub ahead of print]