Multiple myeloma (MM) is an incurable cancer characterized by the clonal proliferation of plasma cells within the bone marrow. Current treatment for most patients with newly diagnosed MM includes induction therapy (typically dexamethasone plus thalidomide or bortezomib for patients eligible for autologous stem cell transplantation [AuSCT], melphalan and prednisone, with or without thalidomide, for those ineligible for transplantation), followed by consolidation with high-dose melphalan and AuSCT for transplant-eligible patients, and finally maintenance therapy. Intensive induction therapy and AuSCT produce superior outcomes in younger patients (<60 years) with Stage II/III MM when compared with patients receiving standard induction therapy. Older patients undergoing AuSCT are more likely to experience physical, gastrointestinal and affective symptoms than younger patients. Cancer and cancer treatment related symptoms involve the actions of proinflammatory cytokines. One of the actions of inflammatory cytokines is to regulate microRNA (miR), small non-coding RNA that can regulate the expression of inflammatory mediators. Therefore, we investigated the relationship between the serum levels of inflammatory mediators (cytokines and relevant miR) and the severity of the self-reported symptoms in MM patients undergoing AuSCT.
This ongoing prospective study consists of sixteen elderly (64.6 yrs ± 6.9 yrs) subjects with stage II/III MM, 10 men and 6 women;12 Caucasian, 3 Hispanic, and 1 African-American. Sera were obtained prior to AuSCT, then biweekly for the first 4 weeks, and at 3 and 6 months to measure levels of interleukin (IL)-1 receptor antagonist (IL-1RA), IL-6, IL-8, and tumor necrosis factor-alpha (TNF-α) by Luminex bead array assay and circulating miR-21 and miR-146a by real-time PCR. Self-reported symptoms were assessed by the MD Anderson Symptom Inventory - multiple myeloma module (MDASI-MM). Non-parametric Spearman's test determined the correlation between the above biomarkers and the symptom scores.
Several self-reported symptoms peaked around nadir (+7 days) including fatigue, poor appetite, drowsiness, nausea, and dry mouth. Whereas IL-6 and IL-8 levels peaked around nadir, IL-1RA and TNF-α levels dropped by nadir and then recovered by 2–4 weeks post AuSCT. There were significantly positive correlations between the serum level of IL-6 and other inflammatory cytokines IL-1RA, IL-8, and TNF-a across the time points of sampling. In addition, serum levels of IL-6 and TNF-a statistically positively correlated with miR-21. Serum IL-6 and IL-10 levels were positively correlated with the mean score of MDASI core symptoms and of MM-related symptoms; whereas the level of miR-21, and not miR-146a, was linearly positively correlated with the mean scores of MDASI-MM symptoms. To our knowledge, this is the first study to report the concordance between serum levels of IL-6 and miR-21, and symptom burden of MM patients. These results suggest that targeting miR involved in cytokine deregulation and disease relapse may provide survival benefit for patients undergoing AuSCT.
Giralt: Celgene: Honoraria, Speakers Bureau; Millenium: Honoraria, Speakers Bureau.