Outcomes in patients with relapsed or refractory multiple myeloma in a phase I study of everolimus in combination with lenalidomide.

Everolimus, an oral mammalian target of rapamycin (mTOR) inhibitor, has been studied in multiple myeloma (MM) but lacks significant single agent activity. Based on preclinical studies showing synergistic activity of mTOR inhibitors with lenalidomide, we studied the combination of lenalidomide and everolimus in relapsed or refractory MM in a phase I clinical trial. We assessed patient samples using gene expression, Western blotting and immunohistochemistry to probe the mTOR pathway. Twenty-six patients were evaluable for toxicity. Dose-limiting toxicities included grade 4 neutropenia and thrombocytopenia. The maximum tolerated dose was lenalidomide 15 mg and everolimus 5 mg for 21 d with a 7 d rest period. Grade 3/4 adverse events included thrombocytopenia (35%) and neutropenia (42%). The overall response rate was 65% (1 complete response + 4 partial response + 10 minimal response). The median progression-free survival was 5·5 months and median overall survival was 29·5 months. Biomarker data demonstrated downregulation of phosphorylated p70S6K. Gene expression profiling suggested activation of mTOR in responders versus non-responders. The combination of lenalidomide and everolimus was well tolerated with predictable toxicities and showed responses in a heavily pretreated population. When confirmed with larger patient numbers, this analysis may guide patient selection for future clinical trials of mTOR inhibition in MM.

Pneumocystis carinii pneumonia in HIV negative patients with primary brain tumors.

BACKGROUND: Pneumnocystis carinii pneumonia (PCP) is an opportunistic infection with rather adverse outcomes. An unexpected increase in cases of PCP was noted in the brain tumor population at the Johns Hopkins Hospital (JHH) in 2000. This prompted the present review of the clinical features and risk factors for PCP in the human immunodeficiency virus (HIV) negative brain tumor population. METHODS: The study was located at the JHH. A retrospective review of medical records was done to identify patients with discharge diagnosis of PCP from 1980 to 2001. Patients who were HIV positive were excluded. A detailed analysis was done of patients with brain tumors. RESULTS: From 1980 to 2001, 468 cases of PCP were identified, diagnosed histologically or clinically, of which 110 were patients with an underlying malignancy. Of the 110 cases 15 were seen in the brain tumor population. Of these, 6 patients were seen in 2000 and one in early 2001. Three of these had primary central nervous system (CNS) lymphoma (PCNSL) on high dose methotrexate. Eight of the fifteen episodes (53.3%) were fatal despite institution of antibiotics and supportive therapy. CONCLUSION: The incidence and mortality due to Pneumocystis carinii among the brain tumor population is increasing. While corticosteroids are known immunosupressants, prescribing patterns for these medications has not changed lately. However, high dose methotrexate is now being used in PCNSL and could be a complicating factor. Since effective prophylaxis exists, it should be considered in patients with brain tumors receiving high dose steroids, high dose methotrexate or with lymphopenia.