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

Abstract

Key Points• REP is an active combination in MM 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/d) and prednisone (20 mg/d). At the MTD (n 5 67 patients), the overall response rate was 67%, and at least minimal response was achieved in 83% of the patients. Median progression-free survival and overall survival 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 fluorescence in situ hybridization. Neutropenia (22%) and thrombocytopenia (22%) were the most common grade 3-4 hematologic adverse events. Infections (21%) were the most common grade 3-5 nonhematologic 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 www.clinicaltrials.gov as

A question of class: Treatment options for patients with relapsed and/or refractory multiple myeloma

“…In a recent phase I/II study in patients who had received multiple previous lines of therapy, the addition of prednisone and lowdose cyclophosphamide to lenalidomide led to an ORR of 67%, a median PFS of 12.1 months and a median OS of 29.0 months. Interestingly, similar results were achieved in the subset of patients with lenalidomide-refractory disease, and in those with bortezomibrefractory disease (Nijhof et al, 2016).…”

How I manage the toxicities of myeloma drugs

“…If temporary treatment with a sedative or hypnotic does not resolve symptoms, substituting dexamethasone with prednisone may be helpful, especially in elderly and/or frail patients. 88 …”

Treatment options for relapsed and refractory multiple myeloma

“…Another strategy that has been examined is the addition of low-dose oral cyclophosphamide to RD in patients progressing during LEN therapy, with reasonable responses. 28 Pomalidomide. POM is a third-generation IMiD agent and the most recently approved antimyeloma drug.…”