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Lenalidomide-based regimens in elderly MM
21 days; oral melphalan 0.18 mg/kg for 4 days in patients 65-75 years old and 0.13 mg/kg in those >75 years of age; prednisone 1.5 mg/kg for 4 days. CPR patients received lenalidomide 10 mg/day for 21 days; oral cyclophosphamide 50 mg every other day for 28 days in patients 65-75 years old and 50 mg every other day for 21 days in those >75 years of age; prednisone 25 mg every other day. After induction, patients were randomized to receive maintenance treatment with lenalidomide alone (R) 10 mg on days 1-21 every 28 days, or in combination with prednisone (RP) 25 mg every other day continuously. After the inclusion of the first 120 patients, the protocol was amended to increment the doses of lenalidomide and cyclophosphamide in patients 65-75 years old in the CPR group, due to negligible toxicities in comparison with those in the two other treatment arms. Therefore, the CPR induc- tion schedule was changed to lenalidomide 25 mg/day for 21 days and oral cyclophosphamide 50 mg/day for 21 days.
Statistical analysis
Updated analyses were performed using data collected on October 31, 2017. All the results were evaluated on an intention- to-treat basis. For univariate analyses, the time-to-event curves were estimated using the Kaplan–Meier method and compared using the log-rank test. Time to event was expressed as median or as 5-year Kaplan–Meier estimate. The Cox proportional hazards model was used to estimate the hazard ratio (HR) values and the 95% confidence intervals (95% CI). Data were analyzed as of May 2018 using R (v3.1.1).
Results
A total of 654 patients were randomly assigned to receive induction with Rd (n=217) or MPR (n=217) or CPR (n=220) (Online Supplementary Figure S1). Baseline demo- graphics and disease characteristics were previously reported10 and were well balanced among the three groups. The median age was 73 years in the Rd and CPR arms, and 74 years in the MPR arm. Twenty-five percent of patients were classified as frail and these patients were evenly distributed among the treatment arms. A total of 402 patients completed the assigned induction treatment and were randomly allocated to receive maintenance with RP (n=198) or R (n=204) (Online Supplementary Figure S1, Table 1 for baseline characteristics).
The median follow-up for survivors was 71 months from enrollment. Progression or death occurred in 177 patients (82%) in the Rd arm, 166 (76%) in the MPR arm, and 194 (88%) in the CPR arm. The median PFS was 18.6 months with the doublet and 20.8 months with the triplet combinations (HR 1.05, 95% CI: 0.87-1.25, P=0.62) (Online Supplementary Figure S2). The median OS was 61.5 months with doublet and 65.7 months with triplet regi- mens (HR 1.09, 95% CI: 0.87-1.37, P=0.47). Comparing the three arms separately, the median PFS was 18.6 months in the Rd arm, 22.2 months in the MPR arm and 18.9 months in the CPR arm (MPR vs. CPR: HR 0.78, 95% CI: 0.63-0.96, P=0.02; MPR vs. Rd: HR 0.84, 95% CI: 0.68- 1.04, P=0.11) (Figure 1A). The median time to next treat- ment (TNT) was 23.8 months in the Rd arm, 28.7 months in the MPR arm and 23.8 months in the CPR arm (MPR vs. CPR: HR 0.79, 95% CI: 0.64-0.98, P=0.03; MPR vs. Rd: HR 0.82, 95% CI: 0.66-1.02, P=0.07) (Figure 1B). The median progression-free survival 2 (PFS-2) was 41.2 months in the Rd arm, 40.2 months in the MPR arm and 40.8 months in the CPR arm (MPR vs. CPR: HR 0.90, 95% CI: 0.72-1.14,
P=0.40; MPR vs. Rd: HR 0.94, 95% CI: 0.74-1.19, P=0.63) (Figure 1C). Death occurred in 115 patients (53%) in the Rd arm, 108 (50%) in the MPR arm and 107 (49%) in the CPR arm. The median OS was 61.5 months with Rd, 65.2 months with MPR and 66.4 months with CPR (MPR vs. CPR: HR 1.03, 95% CI: 0.79-1.35, P=0.83; MPR vs. Rd: HR 0.93, 95% CI: 0.72-1.22, P=0.61) (Figure 1D). The sub- group analysis of induction treatment in patients with standard- and high-risk cytogenetics showed the same trends observed in the overall population (Online Supplementary Figure S3).
A post-hoc analysis according to patients’ frailty was performed (Figure 2). In fit patients, an advantage with the triplet regimen MPR was detected: the median PFS was 21.2 months in patients treated with Rd, 25.6 months in the MPR arm and 21.7 months in patients given CPR (MPR vs. CPR: HR 0.72, 95% CI: 0.52-1.00, P=0.05; MPR vs. Rd: HR 0.72, 95% CI: 0.52-0.99, P=0.04) (Figure 2A). The median OS was 50.2 months in the Rd group, shorter than in both the MPR (79.9 months) and CPR groups (82.9 months) (MPR vs. CPR: HR 1.11, 95% CI: 0.72-1.71, P=0.65; MPR vs. Rd: HR 0.75, 95% CI: 0.50-1.12, P=0.16) (Figure 2B). In intermediate-fit patients, no advantage of one regimen over the others was found: the median PFS was 16.6 months in the Rd arm, 20 months in the MPR arm and 20.9 months in the CPR arm (Figure 2C). The median OS was not reached in the Rd arm, was 60.8 months in the MPR arm and was 66.7 months in the CPR arm (Figure 2D). Not even in frail patients was one regi- men found to be superior to another: the median PFS was 18.2 months in the Rd arm, 21.5 months in the MPR arm and 13.8 months in the CPR arm (Figure 2E). The median OS was 48.2 months with Rd, 44.7 months with MPR and 40.5 months with CPR (Figure 2F).
Table 1. Demographics and baseline characteristics of the patients receiving maintenance treatment.
Patients’ characteristics
Age range, years Median, years >75 years, n (%)
Sex (male), n (%)
Karnofsky score Median
<80, n (%)
Fitness
Fit, n (%) Intermediate-fit, n (%) Frail, n (%)
Creatinine clearance, mL/min
Median, mL/min
Lenalidomide (R) (n=204)
50-89 73
61 (30%)
86 (42%)
60-100 90
37 (18%)
101 (50%) 63 (31%) 40 (20%)
30-168.9 72
Lenalidomide- prednisone (RP) (n=198)
65-87 73
64 (32%)
105 (53%)
60-100 90
43 (22%)
91 (46%) 58 (29%) 49 (25%)
30-150 70
65 (33%) 88 (44%) 45 (23%)
162 (82%) 36 (18%) 37 (19%)
International Staging System score
I, n (%) II, n (%) III, n (%)
65 (32%) 92 (45%) 47 (23%)
Cytogenetic abnormalities by FISH
Data available, n (%) Data missing, n (%) High risk*, n (%)
163 (80%) 41 (20%) 36 (18%)
* At least one among deletion 17p [del(17p)], translocation (4;14) [t(4;14)] or translo- cation (14;16) [t(14;16)]. FISH: fluorescence in situ hybridization.
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