The addition of cyclophosphamide to lenalidomide and dexamethasone in multiply relapsed/refractory myeloma patients; a phase I/II study

Abstract

SummaryWe report the results of a Phase I/II dose escalation study to determine the maximum tolerated dose (MTD) of cyclophosphamide when combined with lenalidomide and dexamethasone in relapsed/refractory myeloma. Thirty-one patients were enrolled in cohorts of 3, at five dose levels of cyclophosphamide to a maximum of 700 mg on days 1 and 8 of a 28-d cycle. Patients received lenalidomide 25 mg days 1-21 and dexamethasone 20 mg orally days 1-4 and 8-11. The MTD was 600 mg cyclophosphamide, days 1 and 8. Grade 3/4 haematological complications occurred in 26% of patients, grade 3/4 infection in 3% (both at 700 mg cyclophosphamide), with thromboembolic complications in 6% of patients. Overall complete response (CR) rate was 29%, very good partial response rate 7% and partial response rate 45% giving an overall response rate of 81%. After 21 months median follow-up, projected 2-year progression-free survival was 56%, with 80% overall survival at 30 months. Ten further patients were treated at MTD with a 40% CR rate. No dose reductions for any study drugs or deaths occurred during cycles 1-9. Lenalidomide, cyclophosphamide and dexamethasone is a safe, effective combination in relapsed myeloma inducing a high response rate, warranting further investigation in phase III trials.

Randomized multicenter phase 2 study of pomalidomide, cyclophosphamide, and dexamethasone in relapsed refractory myeloma

“…This observation is, however, tempered by the small sample size of high-risk patients (15) and the fact that this was an unplanned subgroup analysis. Future studies are needed to validate this observation.…”

“…[9][10][11][12][13][14][15] Interestingly, a combination of lenalidomide and continuous cyclophosphamide resulted in an ORR of 50% in lenalidomide refractory patients, suggesting cyclophosphamide may be able to overcome resistance to lenalidomide in the clinic. 16 In addition, Larocca et al combined continuous pomalidomide with oral cyclophosphamide.…”

Perifosine plus lenalidomide and dexamethasone in relapsed and relapsed/refractory multiple myeloma: a Phase I Multiple Myeloma Research Consortium study

“…Findings may show whether patients with an activated Akt genotype would benefit in particular from the addition of perifosine, therefore raising the possibility of individualized therapy according to a patient's phospho-Akt status. Other Phase I/II studies have investigated whether the addition of a third agent, such as doxorubicin (Knop et al, 2009), vorinostat ), or cyclophosphamide (Schey et al, 2010), can enhance the activity of lenalidomidedexamethasone in patients with relapsed and/or refractory MM. As with the current study, it has been difficult to demonstrate improved efficacy and survival of the 3-drug combinations over the lenalidomide-dexamethasone regimen, due to a lack of comparable patient populations.…”

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

“…35 Other studies have also demonstrated a beneficial effect of addition of weekly cyclophosphamide to lenalidomide and corticosteroids in patients with relapsed/refractory lenalidomide-naive MM ($ PR: 65% to 94%). [40][41][42] Because of the high response and prolonged PFS reported in these studies, directly starting with the 3-drug regimen of lenalidomide, cyclophosphamide, and corticosteroid may also be considered, as opposed to adding cyclophosphamide at the time of development of lenalidomide-refractory disease. Furthermore, a retrospective analysis showed high efficacy ($ PR: 68%) and good tolerability of lenalidomide, low-dose cyclophosphamide, and prednisone in relapsed/refractory MM patients who were previously exposed to lenalidomide-dexamethasone (39% lenalidomide refractory).…”