Phase I/II Study with Single Agent Everolimus (RAD001) in Patients with Relapsed or Refractory Multiple myeloma.

The mammalian target of rapamycin (mToR) plays an important role in multiple myeloma (MM), since it is involved in the PI3K-AKT pathway which can be activated by stimulation with growth and survival factors such as interleukin-6 (IL-6) and insulin-like growth factor-1 (IGF-1) or the loss of the tumor suppressor PTEN. Inhibition of mToR blocked myeloma cell growth in vitro as well as in preclinical animal models. The mToR inhibitor everolimus (RAD001) is approved for immunosuppression and for the treatment of renal cell cancer. In an investigator-initiated phase I/II open label trial, patients ≥ 18 years with relapsed or refractory multiple myeloma (MM) were included after at least two lines of previous treatment. The patients received a fixed dose of oral everolimus for six months. The cohorts had 3 to 6 participants. The phase I part of the trial followed a classical dose-escalation design with three planned dose levels (5 mg, 7.5 mg and 10 mg). Patient benefiting from study drug were allowed to continue with treatment. To obtain insights into the biological activity of everolimus, serum dose levels were monitored and bone marrow biopsies and aspirates were performed three times (at screening, after four weeks and after six months of treatment).

The primary endpoint of the phase I part was safety. Currently, 12 patients were screened and 11 enrolled in the trial (10 male and 1 female, age from 52 to 71 years). One patient withdrew his consent in the first four weeks of treatment and had to be replaced for safety and efficacy assessment. Since no DLT were observed, the intended final daily dose of 10 mg everolimus could be reached. Only one of four SAE during treatment was assessed to be possibly related to the study drug. Except for one grade 4 thrombocytopenia, no > grade 3 AE were observed during treatment. Remarkably, few infectious complications (≤grade 2) were seen despite the known immunosuppressive activity of everolimus. Anti-myeloma activity was documented in 5 out of 7 evaluable patients. One partial response in a heavily pre-treated patient and stable disease in four additional patients were seen. The observed rate of responses and clinical benefit fulfills the criteria defined in the protocol to enter the phase II part of the trial after completing phase I. The individual serum dose levels varied widely and response seemed to correlate to the achieved everolimus dose level.

Everolimus given orally at doses of 5 mg to 10 mg daily showed an acceptable safety profile in heavily pre-treated multiple myeloma patients and the observed responses even at suboptimal dose levels are promising. Further evaluation of everolimus, alone and in combination with other drugs, is warranted.

Guenther:Novartis: Consultancy, Research Funding. Off Label Use: Everolimus is not approved for multiple myeloma. Baumann:Novartis: Consultancy, Research Funding. Schmidmaier:Novartis: Consultancy, Research Funding. Gramatzki:Novartis: Consultancy, Research Funding, Speakers Bureau.