Preliminary Evidences of Circulating Inflammatory Markers Associated with Symptom Development In Patients with Multiple Myeloma During Induction Therapy

Disease progression in multiple myeloma (MM) is highly related to cytokines, particularly interleukin (IL)-6, which promotes the growth of MM and is essential for the proliferation of malignant plasma cells. However, there are few reports delineating the relationship between levels of circulating cytokines and the severity of symptoms that patients experience during induction therapy.

Thirty-four patients with MM were enrolled in this ongoing study before or within 2 cycles of induction therapy (with majority of bortezomib based and few thalidomide based). Multiple symptoms were measured by M. D. Anderson Symptom Inventory – MM module (MDASI-MM) twice a week during induction therapy. Sera were collected at baseline and during every cycle of induction therapy to measure cytokines by Luminex Multiplex Bead Array assay. Using ordinal regression models, we examined the hypothesis that concentration of serum inflammatory cytokines would be associated with symptom burden in patients with MM during induction therapy, especially therapy induced symptoms. The modeling was adjusted for time from induction therapy, age, sex, staging, Eastern Cooperative Oncology Group performance status (PS), opioid use, and body mass index (BMI). Symptom severity ratings were treated as ordinal responses. A log scale of cytokine concentrations was used for modeling.

From longitudinal symptom profile modeling, in general, female patients and patients with poor PS (PS ≥ 2) reported significantly higher level of symptoms than male patients and those with good PS. Overall, the most severe symptoms included fatigue, muscle weakness, sleep disturbance, pain, drowsiness, numbness and bone aches during the induction period. Several sickness symptoms show a trend, although not statistically significant, of decrease during the first cycle of induction therapy. By the end of the first cycle of induction therapy, we observed significant increases in therapy induced symptoms which included numbness, muscle weakness, difficulty remembering, poor attention and diarrhea (all P<0.05). Thereafter, symptoms stabilized or increased in severity for the remainder of induction period (see figure 1 Lowess curves for selected symptoms items on MDASI). Among the panel of inflammatory cytokines and soluble cytokine receptors (sIL-6R and sTNF-R1), monocyte chemoattractant protein, and C-reactive proteindemonstrated statistically significant relationships with severity of the majority of symptoms over time of induction therapy. Because of the non linear trajectory of symptom development, we tested the relationship between symptoms and cytokines by therapy cycle. There were no statistically significant correlations between any symptoms and cytokines (IL-6, IL-8, IL-10, and interferon-gamma, IL-1 receptor antagonist, soluble receptors, and angiogenic factor, vascular endothelial growth factor. On the other hand, sIL-2R, IL-2, and TNF-a were significantly correlated with few symptoms.

Soluble cytokine receptors can play an important role in the development of MM and treatment-related symptoms. Hierarchical dynamic modeling can be used to assess the statistical relationship between biomarkers and the severity of symptoms. With a larger sample, the symptom and cytokine profile by patient's tumor response will be analyzed to address the interaction between cytokines and disease as well as therapy-driven symptom burden. The results of these studies that yield empirical information on expected symptom burden could be very useful for the management of symptoms and improved clinical management of patients.

Figure 1.

Symptom severity profile during induction therapy in MM patients

No relevant conflicts of interest to declare.