Lenalidomide Plus Cyclophosphamide and Prednisone: A Safe, Effective Option for Lenalidomide-Refractory Multiple Myeloma

Patients with multiple myeloma (MM) who are refractory to lenalidomide and bortezomib have limited treatment options and poor outcomes, with a median event-free survival of five months and an overall survival (OS) of nine months. Results of a phase I/II study evaluating lenalidomide plus cyclophosphamide and prednisone (REP) suggest that this combination could be a safe, effective treatment approach for patients with lenalidomide-refractory MM.

“Double-refractory patients have a very poor outcome, but REP induces a high response rate and a relatively long progression-free survival (PFS) in these patients. Furthermore, the combination is fully orally [administered] and was generally well tolerated,” Niels W.C.J. van de Donk, MD, PhD, from VU University Medical Center in Amsterdam, the Netherlands, and corresponding author of the study, told ASH Clinical News. “We think that REP is a good treatment option when patients have lenalidomide-refractory MM or double-refractory MM (disease refractory to both lenalidomide and bortezomib).”

Inger S. Nijhof, MD, also of the VU University Medical Center, and authors conducted this prospective, investigator-initiated, non-randomized, multicenter, open-label study to assess the optimal dose of REP and evaluate the safety of this combination in 82 patients enrolled at 10 hospitals in the Netherlands between August 2001 and November 2014.

Patients with MM were eligible if they were refractory to lenalidomide (defined as progressive disease during therapy, no response to prior lenalidomide-containing therapy, or within 60 days of discontinuation from lenalidomide-containing regimens) following at least one prior therapy.

The median patient age was 66 years (range = 41-82 years), and the median number of prior therapies was three (range = 1-10 treatments). Most patients (n=66; 80%) had progressive disease during lenalidomide-based therapy, while 14 percent (n=11) had progression within 60 days of stopping lenalidomide-containing therapy and 6 percent (n=5) had no response to lenalidomide-containing therapy. In addition, 66 percent of patients (n=54) were refractory to bortezomib.

Lenalidomide was administered on days one through 21 of a 28-day cycle, and cyclophosphamide and prednisone given continuously until disease progression.

According to results from the phase I, dose-finding trial, in which 21 patients were treated at five different dose levels, the maximum-tolerated dose (MTD) of REP was determined to be lenalidomide 25 mg and cyclophosphamide 50 mg/day plus prednisone 20 mg/day.

In the phase II expansion safety and efficacy study, 61 new patients were enrolled, as well as seven patients who had been treated with the MTD in phase I.

Patients received a median of nine REP cycles (range = 1-30 cycles).

The most common hematologic adverse event (AE) was grade 3 (n=13; 19%) and grade 4 (n=2; 3%) neutropenia. Grade 3 anemia occurred in 4 percent of patients, while grade 3 (n=10; 15%) and grade 4 (n=5; 7%) thrombocytopenia also occurred. The most common non-hematologic AEs included infections (grade 3 = 18%), mostly upper and lower respiratory tract infections, as well as pneumonia with septic shock (n=2; 3%), and cardiac disorders (n=5). No second primary malignancies were observed.

Treatment-related AEs resulted in at least one level of dose reduction of lenalidomide in 11 patients (16%), but no dose reductions for cyclophosphamide or prednisone were required. Eight patients (12%) discontinued therapy due to AEs.

After a median follow-up of 24.5 months (range = 1.1-33.9 months), the median PFS was 12.1 months, and the median OS was 29 months. The authors observed an overall response rate (ORR; primary endpoint) of 67 percent and a clinical benefit rate (minimal response [MR] or better) of 82 percent. See TABLE on page 40 for treatment outcomes with the MTD of REP.

Patients who experienced a partial response (PR) or better or a very good PR (VGPR) or better had significantly longer median PFS than those with responses less than PR: 15.6 months and not reached, respectively, versus 3.7 months (p value not provided). Notably, the median PFS with REP appeared to be longer than the median with previous lenalidomide-containing therapy (11.2 months).

OS was also longer for patients who achieved PR (29 months) or VGPR (30.9 months) compared with less than PR (median OS = 11.9 months), but this did not reach statistical significance (p value not provided).

Looking at potential prognostic factors for a better response to REP, the authors found that response was similar between patients with high- and standard-risk cytogenetics (median PFS = 12.1 vs. 12.3 months [p=0.943]; median OS = 22.3 vs. 29 months [p=0.982]). Refractory status also did not affect response, with response rates, PFS, and OS similar to patients who were double-refractory to lenalidomide and bortezomib and those who were not refractory to bortezomib.

The only factor significantly associated with response was World Health Organization performance status prior to REP therapy; patients with scores of 2 or 3 had a significantly lower response rate than those with a score of 0 or 1 (p=0.01).

The study is limited by its small patient population and non-randomized design. And, although he called the results encouraging, Dr. van de Donk noted that “a phase III trial would be required to definitely prove the advantage of REP versus low-dose cyclophosphamide plus prednisone alone.”

In addition, the authors noted, “It is currently unclear whether weekly higher-dose cyclophosphamide has the same effects on the bone marrow microenvironment and the same activity in patients when compared [with] continuous low-dose cyclophosphamide. Additional studies are needed to resolve these questions.”


Nijhof IS, Franssen LE, Levin MD, et al. Phase 1/2 study of lenalidomide combined with low-dose cyclophosphamide and prednisone in lenalidomide-refractory multiple myeloma. Blood. 2016 September 19. [Epub ahead of print]

TABLE. Responses Treated at the Maximum-Tolerated Dose
  All patients (lenalidomide-refractory; n=66) Lenalidomide- and bortezomib-refractory patients (n=42) Patients with high-risk cytogenetic abnormalities* (n=24) Patients treated with REP, directly following the development of lenalidomide-refractory disease (25 mg or equivalent in case of renal insufficiency; n=46)
Stringent complete response (CR) 1.5% 0% 0% 0%
CR 3% 2.4% 0% 0%
Very good partial response (VGPR) 18.2% 21.4% 20.8% 15.2%
Partial response (PR) 44% 36.1% 45.9% 50%
Minimal response (MR) 16.6% 21.1% 16.6% 17.4%
Stable disease 7.6% 9.5% 4.2% 10.9%
Progressive disease 9.1% 9.5% 12.5% 6.5%
≥VGPR 22.7% 23.8% 20.8% 15.2%
≥PR 66.7% 59.9% 66.7% 65.2%
≥MR 83.3% 81% 83.3% 82.6%
REP = lenalidomide plus continuous low-dose cyclophosphamide and prednisone

*High-risk disease was defined by the presence of t(4;14), t(14;16), del(17p), and/or amp1(1q) as determined by fluorescence in situ hybridization on purified multiple myeloma cells before start of REP treatment.