title: Activity of everolimus (RAD001) in relapsed and/or refractory multiple myeloma: a phase I study.
abstract: The mammalian target of rapamycin plays an important role in multiple myeloma. The allosteric mammalian target of rapamycin inhibitor everolimus has long been approved for immunosuppression and has shown activity in certain cancers. This investigator-initiated phase I trial explored the use of everolimus in relapsed and/or refractory multiple myeloma patients who had received two or more lines of prior treatment. Following a dose-escalation design, it called for a fixed dose of oral everolimus. Blood drug levels were monitored and the biological activity of everolimus was evaluated in bone marrow. Seventeen patients were enrolled (age range, 52 to 76 years). All had been previously treated with stem cell transplantation and proteasome inhibitors and almost all with immunomodulatory drugs. No dose-limiting toxicity was observed and the intended final daily dose of 10 mg was reached. Only one severe adverse event was assessed as possibly related to the study drug, namely atypical pneumonia. Remarkably few infections were observed. Although the trial was mainly designed to evaluate feasibility, anti-myeloma activity, defined as clinical benefit, was documented in ten of 15 evaluable patients at every dose level including eight patients with stable disease, one patient with minor remission and one with partial remission. However, the median time to progression was 90 days (range, 13 to 278 days). The biomarker study documented on-target activity of everolimus in malignant plasma cells as well as the microenvironment. The observed responses are promising and allow further studies to be considered, including those testing combination strategies addressing escape pathways. This trial is registered with EudraCT number 2006-002675-41.
authors: Division of Stem Cell Transplantation and Immunotherapy, 2 Department of Medicine, University of Kiel, Germany a.guenther@med2.uni-kiel.de.
authors: Andreas
authors: A
authors: Günther
authors: Medizinische Klinik und Poliklinik IV, Klinikum der Ludwig-Maximillians-Universität München (LMU), Germany.
authors: Philipp
authors: P
authors: Baumann
authors: Division of Stem Cell Transplantation and Immunotherapy, 2 Department of Medicine, University of Kiel, Germany.
authors: Renate
authors: R
authors: Burger
authors: Division of Stem Cell Transplantation and Immunotherapy, 2 Department of Medicine, University of Kiel, Germany.
authors: Christian
authors: C
authors: Kellner
authors: Division of Hematopathology, Institute of Pathology, University of Kiel, Germany.
authors: Wolfram
authors: W
authors: Klapper
authors: Medizinische Klinik und Poliklinik IV, Klinikum der Ludwig-Maximillians-Universität München (LMU), Germany.
authors: Ralf
authors: R
authors: Schmidmaier
authors: Division of Stem Cell Transplantation and Immunotherapy, 2 Department of Medicine, University of Kiel, Germany.
authors: Martin
authors: M
authors: Gramatzki
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D015415:Biomarkers; D001706:Biopsy; D001853:Bone Marrow / Q000473:pathology; D000068338:Everolimus; D005260:Female; D006801:Humans; D056747:Immunomodulation / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology*; D009364:Neoplasm Recurrence, Local; D009367:Neoplasm Staging; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D015415:Biomarkers; D007166:Immunosuppressive Agents; D000068338:Everolimus; D020123:Sirolimus