Secondary malignancies in elderly myeloma patients

Advances in cancer detection and treatment have tripled cancer survivorship since 1971, and the population of cancer survivors has grown by 2% each year (Travis et al, 2006). However, longer survival increases the risk of second primary malignancy (SPM) development in these patients, possibly through late sequelae of treatment, aging, and/or genetics (National Cancer Institute; Fraumeni et al, 2006). Among these, age is a well-characterized risk factor for primary malignancy development, and data from the Italian region demonstrate increased incidence rates per year of life for each 10-year age group studied: 0.40% (ages 45- 54), 0.97% (ages 55-64), 1.82% (ages 65-74), 2.54% (ages 75-84), and 3.86% (ages 85+). The risk of SPM development should be reported as SPM incidence per year of follow-up, and age should be considered a risk factor. Multiple myeloma (MM) is an incurable malignancy characterized by multiple relapses, and eventually, refractory disease and death. Therapy advances have resulted in significant survival benefits, with 5- year relative survival rates among patients with MM of all age groups having increased from 26% to 38% for patients first diagnosed in 1975- 1977 and 1999-2006, respectively (Travis et al, 2006). In these patients, prolonged survival may increase the risk of developing an SPM. Registry studies conducted in the United States and Sweden have shown that MM patients are at a higher risk for the development of non-Hodgkin's lymphoma (NHL; 1.7-fold), acute myeloid leukemia (AML; 8-fold), and chronic myeloid leukemia (CML; 2.5-fold) compared with all cancer patients (Dores et al, 2006; Dong et al, 2001). The goal of this presentation is to discuss the issue of SPM emergence in recent clinical trials evaluating the use of lenalidomide in autologous stem cell transplant (ASCT)-eligible and -ineligible patients with newly diagnosed MM (NDMM). The current report describes SPM incidence in patients enrolled in MM-015 as well as spontaneous SPM reports from investigators for additional investigator sponsored trials. MM-015 is a phase 3 trial designed to evaluate the efficacy and safety of continuous lenalidomide treatment (melphalan, prednisone, and lenalidomide induction followed by lenalidomide maintenance [MPR-R]) vs fixed-duration regimens of melphalan and prednisone (MP) or melphalan, prednisone, and lenalidomide (MPR) in transplant-ineligible patients aged > 65 years. A post hoc analysis evaluated incidence rates (IRs) per 100 person-years for SPMs and risks of SPM relative to disease progression risk. As of the May 2010 data cut-off prior to site-unblinding (median follow-up: 25 months), 12 total cases of SPMs were reported (4/150 in MPR-R [IR = 1.40], 6/152 in MPR [IR = 2.05], and 2/153 in MP [IR = 0.67]), including 2 myelodysplastic syndromes (MDS) cases in MPR-R and 2 AML cases in each of MPR-R and MPR arms. In the MPR/MPR-R vs MP group, the incidence of AML/MDS was 3.6% vs 0.7%, respectively. A longer follow-up is needed to draw definite conclusions. Solid tumors were reported in 6 patients (1/150 in MPR-R, 3/152 in MPR, and 2/153 in MP) and were of heterogeneous tumor types. No B-cell malignancies were reported. Of note, the early detection of some solid tumors may end up in their cure. The progression-free survival (PFS) benefit afforded by lenalidomide maintenance outweighs the increased SPM risk, as indicated by increased progression risk for MP and MPR vs MPR-R. The median PFS for MPR-R vs MP was 31 vs 13 months (P <.001), resulting in a 60% reduction in the risk of disease progression (hazard ratio [HR] = 0.395) (Palumbo et al, ASH 2010). Similarly, 2-year PFS rates were higher for patients receiving MPR-R vs MP (55% vs 16%) (Palumbo et al, ASH 2010). The impact of relapse and the occurrence of a second cancer on patient outcomes has been evaluated. For patients receiving lenalidomide maintenance (MPR-R), the risk of death or progression at 2 years is 45% and the risk of SPM at 2 years is 3%. In patient receiving MP alone the risk of death or progression at 2 years is 84% and t e risk of developing an SPM for these patients at 2 years is 65 years were randomly assigned to receive treatment with either lenalidomide plus low-dose dexamethasone (Rd), MPR, or cyclophosphamide-lenalidomide plus low-dose dexamethasone (CRd). To date, after a median follow-up of 8 months, no SPMs were reported. In a previously published study evaluating lenalidomide as consolidation- maintenance following bortezomib, adriamycin, and dexamethasone (PAD) induction and ASCT in NDMM patients (Palumbo et al, JCO 2010), 102 patients (median age 67) received lenalidomide maintenance and 2 cases of SPMs were reported. In another EMNTG study comparing MPR with tandem melphalan 200 mg/m2 (MEL200) and ASCT (Palumbo et al, ASH 2010), 402 patients <65 years of age were included, and after 2 years of follow-up 2 cases of SPM were reported. In a phase 3 study (343 patients) comparing cyclophosphamide-lenalidomide- dexamethasone (CRD) with MEL200 followed by ASCT, no SPMs were reported. On the contrary, one case of SPM was detected in a GIMEMA phase 2 study evaluating the role of MPR-R as induction in elderly NDMM (54 patients; Palumbo et al, JCO 2007). A total of 46 NDMM patients were enrolled in a study assessing the role of lenalidomide- prednisone (RP) as induction followed by MPR and no SPM cases were reported. The rates of SPM reported here are those currently available in our database; they may be underestimated due to the lack of a specific query on SPM to the participating centers. Efforts are currently ongoing and specific queries are requested to update the incidence of SPM in these studies. Results will be presented at the meeting.