Abstract

Background Multiple myeloma is a cancer of plasma cells that is associated with severe immunodeficiency and increased numbers of bacterial infections. The Tackling Early Morbidity and Mortality in Myeloma (TEAMM) trial assessed the use of prophylactic levofloxacin in newly diagnosed multiple myeloma patients. Interactions between multiple myeloma disease activity, immunity and infection are central to the TEAMM trial. Active multiple myeloma suppresses immunity and infections delay administration of anti-multiple myeloma therapy. Furthermore, infection-derived inflammation nurtures multiple myeloma activity and resistance to anti-multiple myeloma therapy. Objectives The aim of this study was to measure biomarkers of (1) immune competence to develop risk stratification of patients for infection to personalise the decision to prescribe antibiotics, (2) myeloma activity to sensitively measure speed and depth of myeloma response and (3) inflammation to identify patients who may be at risk of poor treatment responses. Method Serum samples were collected from 977 TEAMM trial patients (aged 35–90 years) at randomisation, then every 4 weeks for 16 weeks and again at 1 year. Biomarker levels were compared with samples from healthy controls. Multiplex Luminex® assays (R&D Systems, Minneapolis, MN, USA) and enzyme-linked immunosorbent assays were used for the analysis of biomarkers and anti-viral antibodies were measured by a haemagglutination assay. Results At baseline, levels of both polyclonal immunoglobulins and anti-bacterial antibodies were below the normal range in most TEAMM trial patients. This immunoparesis was much more severe for antibodies against specific bacterial targets than for total immunoglobulin levels. Levels of anti-bacterial antibodies were below the threshold of protection for 18 of the 19 bacterial antigens tested. More patients aged < 65 years were protected against meningococcal serotypes, Haemophilus influenza type b and tetanus, whereas more patients aged ≥ 65 years were protected against pneumococcal serotypes but there was good protection in only 6% of the TEAMM trial patients. Higher levels of polyclonal immunoglobulins, but not specific anti-bacterial antibodies, were found to be associated with a lower risk of infection and a longer survival. At presentation, levels of neutrophil elastase, calprotectin and interleukin 10 were elevated in TEAMM trial patients, compared with healthy controls. Interleukin 10 levels were related to infection during the trial: patients with interleukin 10 levels ≥ 10 pg/ml had a greater risk of infection than patients with interleukin 10 levels < 10 pg/ml. Levels of soluble CD138 were elevated in 72% of TEAMM trial patients and were decreased in response to therapy, with a complete response seen in 40% of TEAMM trial patients by 16 weeks. Of the 76 TEAMM trial patients achieving a free light chain complete response at 16 weeks, only 30% had a soluble CD138 complete response. Overall, responses in the levels of soluble CD138 did not correlate with free light chain and myeloma monoclonal protein (also known as m-protein) responses, consistent with the fact that soluble CD138 responses reflect a separate aspect of disease activity and clonal size. Levels of procalcitonin were elevated in only 50% of patients who had febrile episodes during the TEAMM trial. Although levels of interleukins 6 and 8 at presentation were lower than in a heathy cohort of patients, lower levels of interleukin 6 were identified at baseline in poor responders than in good responders, and in patients who had febrile and non-febrile infections during the trial than in patients who had only non-febrile episodes. Conclusion Information from this Efficacy and Mechanism Evaluation project can help inform risk stratification and patient identification strategies to be responsive to individual patient needs. Monitoring levels of free light chains and soluble CD138 can help identify non-responders early and monitoring interleukin 10 levels can help stratify patients for risk of infection. Furthermore, immunisation in remission should be tested. Limitations The TEAMM trial administered prophylactic antibiotics or placebo for 12 weeks from a new diagnosis of myeloma. Patients were monitored for infections for 16 weeks post diagnosis, with a final set of clinical data gathered at 1 year. Infection data and efficacy of prophylactic antibiotics are available for only the first 16 weeks and survival for the first 52 weeks. This limits long-term data, particularly for progression-free and overall survival. Future work The TEAMM 2 trial (in preparation) will explore the benefit of prophylactic antibiotics up to 12 months following diagnosis and will explore infection risk post therapy and during remission. Furthermore, some of the key findings will be applied to investigate biomarkers in samples from other UK myeloma trials in which long-term outcome data are available. Trial registration Current Controlled Trials ISRCTN51731976. Funding This project was funded by the Efficacy and Mechanism Evaluation programme, a Medical Research Council and National Institute for Health Research (NIHR) partnership, and will be published in full in Efficacy and Mechanism Evaluation; Vol. 7, No. 10. See the NIHR Journals Library website for further project information.