Morrow, Gary R.

Abstract Abstract 3017 Introduction: Multiple myeloma (MM) is a malignancy of clonal plasma cells with resulting in an increase production of ineffective immunoglobulins with suppression of non-involved immunoglobulins. Patients with MM are at increased risk of infectious complications, particularly to those organisms in which opsonization is one of the key defense mechanisms, e.g. strep and staph infections. Treatment of MM is virtually always associated with further immunosuppression, at least in the immediate term, until the malignant clone is eradicated and normal immunoglobulins are produced. Rationale: Due to further compromise of an already incompetent immune system by initial chemotherapy and the previous suggestion (Oken et al Am J Med 1996; 100:624-628) that prophylactic antibiotics may reduce infectious complications, this study was designed to evaluate the impact of prophylactic antibiotics on the incidence of serious bacterial infections during the first two months of treatment. Methods: Pts with untreated MM receiving chemotherapy were randomized on a 1:1:1 basis to receive either a daily ciprofloxacin (C; 500 mg), trimetheprim-sulfamethoxazole (T; DS bid) or observation (O) for the first 2 months of treatment. Pts were evaluated for serious bacterial infection (grade 3 or 4) during the first two months of myelotoxic/suppressive therapy. Secondary endpoints (EP) included: incidence of non-bacterial infections, resistant organisms due to prophylaxis, the incidence of infection the third month OFF of antibiotic prophylaxis and whether protection against infection is associated with an improved response rate. Results: From July 1998 to January 2008, 212 untreated, symptomatic MM pts being treated with myelotoxic/suppressive chemotherapy were randomized to C (n=69), T (n=76) or O (n=67) for the first 2 months of treatment. The incidence of serious infection (> grade 3 ECOG toxicity criteria and/or hospitalization) was comparable among groups: C=10 (14.7%), T=5 (6.9%), O=9 (14.5%); p= 0.268 which was the primary EP. The incidence of any infection during the first 2 months was also comparable (20% vs 23% vs 22%, respectively, p=0.910). There were 25 grade 2 infections and 4 grade 3 infections involving respiratory (n =13), sepsis/bacteremia (n = 4), and urinary (n =3), joint/bone (n =2), unknown (n =2) or various GI tract (n = 5) and skin (n =1). Eight pts expired within the first 2 months: 2 from MM, 3 cardiac, 2 respiratory, 1 renal (unrelated to MM or Rx) occurring in the C (4), T (1), O (2). Secondary EPs failed to show a difference in the incidence of serious bacterial infection during the third month in the absence of prophylaxis (C=3%, T=4%, O=2%; p=0.874), development of resistant infections, initial response to therapy or overall survival. Conclusions: The use of prophylactic antibiotics did not decrease the incidence of serious infection (> grade 3 and/or hospitalization) nor of any infection within the first 2 months of treatment. Infection prophylaxis did not affect the incidence of infection upon completion of 2 months of therapy (nor, ultimately, at any time during the subsequent 2 years), the response to therapy or to overall survival. Incidentally, there were no documented cases of PCP despite the assumption that MM pts, with compromised immune systems, are more susceptible. The incidence of serious infections in this study, in which few patients received novel agents, is comparable to that observed in more modern regimens even in the presence of mandated/recommended prophylactic antibiotics. Utilizing either lenalidomide plus dexamethasone or clarithromycin, lenalidomide and dexamethasone resulted in > grade 3 infectious complications in 16.7% and 9.7%, respectively, as reported by the Mayo Clinic and Cornell groups, respectively (Gay et al Am J Hematol, in press). Furthermore, in the ECOG E4A03 randomized trial of lenalidomide plus either high dose dexamethasone (LD) or low dose dexamethasone (Ld) in which prophylactic antibiotics were recommended, the incidence of > grade 3 infectious complications were 9.4% and 6.4%, respectively (Rajkumar et al Lancet Oncol 2010; 11: 29–37). We conclude that routine use of prophylactic antibiotics should not be mandated for patients receiving induction chemotherapy. Prophylactic antibiotics should be considered on a case-by-case basis after analyzing the potential infection risk in individuals. Disclosures: No relevant conflicts of interest to declare.

Patient-reported outcomes (PROs) are often the primary end point in symptom management trials. The scientific field of PROs is evolving, as evidenced by the US Food and Drug Administration's February 2007 release of a draft guidance for using PROs in effectiveness claims for drug labeling. This article presents issues encountered during use of PROs in National Cancer Institute–sponsored symptom management trials. Selected trials are presented that exemplify the challenges often seen in symptom management trials, and solutions are described. The examples presented include defining the appropriate end point, selecting and validating assessments, and answering the research questions through statistical analysis and interpretation. Progress has been made in addressing some of the unique challenges of PRO-based symptom management research. Many challenges still remain, but a foundational body of work now exists for more consistent and rigorous application of PROs into symptom management trials. There remains a need for more research in several methodologic aspects of design, analysis, and interpretation of symptom management trials.