Phase 1/2 study of lenalidomide combined with low-dose cyclophosphamide and prednisone in lenalidomide-refractory multiple myeloma

Inger S. Nijhof, Laurens E. Franssen, Mark-David Levin, Gerard M.J. Bos, Annemiek Broijl, Saskia K. Klein, Harry R. Koene, Andries C. Bloem, Aart Beeker, Laura M. Faber, Ellen van der Spek, Paula F. Ypma, Reinier Raymakers, Dick-Johan van Spronsen, Peter E. Westerweel, Rimke Oostvogels, Jeroen van Velzen, Berris van Kessel, Tuna Mutis, Pieter Sonneveld, Sonja Zweegman, Henk M. Lokhorst and Niels W.C.J. van de Donk

Key points

  • Lenalidomide-cyclophosphamide-prednisone (REP) is an active combination in multiple myeloma patients refractory to lenalidomide.

  • REP is an all oral and generally well tolerated regimen.


The prognosis of multiple myeloma (MM) patients who become refractory to lenalidomide and bortezomib is very poor, indicating the need for new therapeutic strategies for these patients. Next to the development of new drugs, the strategy of combining agents with synergistic activity may also result in clinical benefit for patients with advanced myeloma. We have previously shown in a retrospective analysis that lenalidomide combined with continuous low-dose cyclophosphamide and prednisone (REP) had remarkable activity in heavily pretreated, lenalidomide-refractory MM patients. To evaluate this combination prospectively, we initiated a phase 1/2 study to determine the optimal dose and to assess its efficacy and safety in lenalidomide-refractory MM patients. The maximum tolerated dose (MTD) was defined as 25 mg lenalidomide (days 1-21/28 days), combined with continuous cyclophosphamide (50 mg/day) and prednisone (20 mg/day). At the MTD (n=67 patients), the overall response rate was 67%, and at least minimal response was achieved in 83% of the patients. Median PFS and OS were 12.1 and 29.0 months, respectively. Similar results were achieved in the subset of patients with lenalidomide- and bortezomib-refractory disease as well as in patients with high-risk cytogenetic abnormalities, defined as t(4;14), t(14;16), del(17p), and/or ampl(1q) as assessed by FISH. Neutropenia (22%) and thrombocytopenia (22%) were the most common grade 3-4 hematologic adverse events. Infections (21%) were the most common grade 3-5 non-hematologic adverse events. In conclusion, the addition of continuous low-dose oral cyclophosphamide to lenalidomide and prednisone offers a new therapeutic perspective for multidrug refractory MM patients. This trial was registered at as #NCT01352338.

  • Submitted July 20, 2016.
  • Accepted September 12, 2016.