445 patients were accrued (); 223 were randomly assigned to receive lenalidomide plus high-dose dexamethasone and 222 to receive lenalidomide plus low-dose dexamethasone. 149 patients (67%) in the high-dose group had bone disease at baseline compared with 127 (57%) of 222 in the low-dose group. 422 patients were eligible for analysis (). As of December, 2008, 404 (91%) of 445 patients are off study
Characteristics of participants
Median duration of therapy was 4 months (95% CI ·7–4·7) in the high-dose group and 6 months (4·9–7·8) in the low-dose group. 21 (14%) of 223 patients in the high-dose group remained on treatment for more than 1 year compared with 66 (30%) of 222 patients in the low-dose group. The mean relative dose intensity of lenalidomide delivered in the first four cycles was 91·1% of the targeted dose in the high-dose group and 91·5% in the low-dose group; the intensity for dexamethasone was 87·2% and 95·7%, respectively. Because the study was designed as an induction trial and patients were allowed to go off-study to pursue autologous stem-cell transplantation, 167 patients interrupted or stopped treatment to have stem-cell harvest. Of these patients, 163 (98%) were successful and four (2%) were unsuccessful.
The overall (complete plus partial) response to therapy after four cycles was higher with high-dose dexamethasone than with low-dose, 169 (79%) of 214 patients on high-dose dexamethasone had an overall response (complete or partial) compared with 142 (68·3%) of 208 on low-dose (p=0·008). The difference in response rates between high-dose and low-dose was 10·7% (two-sided asymptotic 80% CI 6·8–20·8). Although this is lower than 15%, the odds ratio for response of 1·75 (80% CI 1·30–2·32) indicates that low-dose therapy is inferior in terms of overall response rate after four cycles because the preplanned inferiority odds ratio of 1·91 is well within the CI. 90 (42%) patients achieved complete response or very good partial response in the high-dose dexamethasone group in the first four cycles of therapy compared with 49 (24%) patients in the low-dose treatment group (p<0·0001; webappendix). Disease progression within the first four cycles of therapy was low in both groups, noted in eight (4%) of 214 patients receiving lenalidomide plus high-dose dexamethasone and five (2%) of 208 receiving lenalidomide plus low-dose dexamethasone. 20 patients (five from the high-dose group and 15 from the low-dose group) who progressed or did not achieve a response in either group were enrolled to treatment with thalidomide plus dexamethasone; only one minor response was observed among 11 eligible patients (two and nine from the two groups). Nine patients were ineligible because they were enrolled to receive thalidomide incorrectly.
Overall survival was not a protocol-specified endpoint in this study. However, the study was stopped on recommendations of the independent data monitoring committee at a median follow-up of 12·5 months (95% CI 11·5–14·6) because overall survival was significantly higher with low dose than with high-dose dexamethasone (; log-rank p=0·0002). The 1-year overall survival was 96% (95% CI 94–99) in the low-dose group compared with 87% (82–92) in the high-dose group; 2-year overall survival was 87% (81–93) and 75% (68–93), respectively. We studied the effect of the following variables on survival in univariate analysis: treatment group, international staging system (stage 2 or 3 vs 1 and missing vs stage 1), ECOG performance status (>0 vs 0), presence or absence of bone disease, race (white vs other), haemoglobin (≤110 g/l. vs >110 g/l.), serum creatinine (>15 mg/L vs ≤15 mg/L), and age (<65 years vs ≥65 years). These analyses, including outcome assessment by race and sex, were done post hoc and were not prespecified in the protocol. Bone disease, haemoglobin, serum creatinine, and race were not significant on univariate analysis. On a multiple regression analysis of variables significant (p<0·05) in the univariate analysis (treatment arm, international staging system, ECOG performance status, and age) and race, which was borderline significant (p=0·08), the difference in overall survival between the treatment groups remained significant (p=0·001; ). Differences in overall survival were noted in patients age less than 65 years (p=0·01) and those age 65 years and older (p=0·004). Among those age less than 65 years, 1 year overall survival rate was 91% (95% CI 85–97) with high-dose dexamethasone and 98% (92–99) with low-dose dexamethasone. 1-year overall survival rates for those age 65 years and older were 83% (76–90) with high-dose and 94% (89–99) with low-dose. All patients in the high-dose group were instructed to cross-over to low-dose immediately (March 27, 2007).
Overall survival in patients receiving lenalidomide and either high-dose or low-dose dexamethasone
Multivariate analysis of overall survival
With the current median follow-up of 35·8 months (95% CI 35·1–36·3) as of December, 2008, the best overall response rates on each group () show better response with lenalidomide plus high-dose dexamethasone (median response duration 21·4 months, 95% CI 19·7–27·8) than with lenalidomide plus low-dose dexamethasone (24·1 months, 21·5–28·1). Among patients who responded, median time to partial response or better was 1 month. Only five patients in the study (two in the high-dose group and three in the low-dose group) who achieved minor response by four cycles converted to partial response or better with longer therapy. Although the overall response rate did not improve, the level of response of patients with partial response improved with longer duration of therapy (data not shown). The higher response rates for high-dose dexamethasone did not translate into superior progression-free survival (): median progression-free survival was 19·1 months (15·7–26·3) with high dose versus 25·3 months (22·3–not reached) with low-dose (p=0·026). 93 patients progressed in the high-dose group compared with 70 in the low-dose group. Over 2 years of follow-up, 16 of 222 patients died without progression in the high-dose group compared with four of 217 in the low-dose group. 77 patients in the high-dose group progressed compared with 66 of 217 in the low-dose group. Median times to progression were 22·3 months (15·9–36·4) in the high-dose group and 26·1 months (22·3–not reached) in the low-dose group (p=0·298). After 24 months, additional follow-up since crossover to low-dose dexamethasone was done, overall survival curves converge at 3 years (; p=0·467). Median overall survival has not been reached. 56 (25%) of 223 patients in the high-dose group and 53 (24%) of 222 in the low-dose group have died.
Best overall response to therapy
Survival, progression, and death during extended follow-up in patients receiving lenalidomide and either high-dose or low-dose dexamethasone
The most common cause of death was progressive disease, which caused 35 (63%) of 56 deaths in the high-dose group and 37 (70%) of 53 deaths in the low-dose group. Other common causes of death were thromboembolic events, which caused five (9%) deaths in the high-dose group and one (2%) in the low-dose group; infection, which caused four (7%) and three (6%), respectively; and cardiac complications, which caused six (11%) and two (4%), respectively (webappendix).
We did landmark analyses to determine the effect of stem-cell transplantation and outcome of patients who continued the primary therapy in either group. Of 431 patients alive at the 4-month landmark analysis point, 183 discontinued from the study, whereas 248 continued primary therapy beyond 4 months. Of the 183 patients who discontinued from the study at 4 months, 93 (median age 69 years, range 38–87) did not pursue stem-cell therapy as recommended by the protocol (group 1); 3-year overall survival in this group was 55% and did not differ between those receiving high-dose and low-dose therapy (log-rank p=0·631; ). Of the 93 patients, 16 of 54 in the high-dose group and 14 of 39 in the low dose group pursued other treatment options with bortezomib or alkylator-based therapy; the rest stopped therapy at that point and had not received alternative treatment at the time of analysis. 2-year progression-free survival was 25% in both groups. The remaining 90 patients (57 years, 37–53) had autologous stem-cell transplantation and are a cohort of patients who had four cycles of induction with lenalidomide plus dexamethasone followed by transplantation (group 2). 3-year overall survival in this group was 92% and did not differ between treatment groups (log-rank p=0·528; ). 2-year progression-free survival was 63% with high dose and 65% with low-dose dexamethasone. Among the 431 patients in the landmark analysis, 50 (24%) of 212 patients on high-dose and 40 (18%) of 219 on low-dose dexamethasone received autologous stem-cell transplantation at 4 months.
Landmark analysis of overall survival
248 patients (median age 66 years, range 35–87) continued on primary therapy beyond 4 months (group 3), 108 in the high-dose dexamethasone group (65 years, 36–87) and 140 in the low-dose dexamethasone group (66 years, 36–84). 3-year overall survival in these 248 patients was 79% (). 3-year progression-free survival in this group was 46% with high-dose and 50% with low dose dexamethasone. Of 140 patients who received primary therapy with low-dose dexamethasone (median duration of therapy 11·2 months, range 10·2–12·1), 119 (91%) of 131 eligible patients responsed, 29 (22%) had immunofixation-negative complete response, and 75 (57%) had either complete or very good partial responses. The decision point at 4 months on discontinuing the study and pursuing autologous stem-cell transplantation was made by patients’ choice and physician discretion on the basis of age and other factors including response status and toxicity rate. At 4 months, 15 (18%) of 84 patients in group 1, 29 (33%) of 89 in group 2, and 92 (39%) of 237 in group 3 had complete or very good partial response. Grade 4 or higher toxicity was recorded in 16 (17%) of 92 patients in group 1, four (4%) of 90 group 2, and 17 (7%) of 248 in group 3.
Toxicities were most common with high-dose dexamethasone. shows the most common grade 3 or higher adverse events anytime during the course of therapy for the 443 patients assessed for toxicity. 56 (27%) of 223 patients in the high-dose group and 37 (19%) of 222 in the low-dose group discontinued treatment due to adverse events (). 57 (26%) of 223 patients in the high-dose group and 27 (12%) of 220 in the low-dose group had deep-vein thrombosis (p=0·0003); 20 (9%) and nine (4%) of these patients had pulmonary embolism. The incidence of deep-vein thrombosis in patients treated on the protocol after the start of mandatory prophylaxis was unchanged, and might be related to the fact that most patients were already compliant about prophylaxis even before the amendment. Most thromboembolic events occurred in the first 4 months; 45 (20%) of 223 in the high-dose group and 19 (9%) of 220 in the low-dose group had deep-vein thrombosis within the first four treatment cycles.
Major grade 3 or higher toxicity