Abstract
Background: In the pivotal phase 3 FIRST trial, continuous lenalidomide plus low-dose dexamethasone (Rd) improved progression-free survival (PFS), overall survival (OS), and response compared with fixed-duration treatment (Tx) with either Rd or the combination of melphalan-prednisone-thalidomide (MPT) in transplant-ineligible NDMM pts (Facon, Blood 2013). Here we examine if pts achieving complete remission (CR) or at least very good partial response (≥ VGPR) equally benefit from continuous Rd.
Methods: Pts were randomized to continuous Rd until progressive disease (PD; N= 535); Rd for 18 cycles (72 weeks) (Rd18; N = 541); or MPT for 12 cycles (72 weeks) (N = 547). The primary endpoint was PFS (continuous Rd vs. MPT). The secondary endpoints included OS, response rate (assessed using IMWG criteria), time to response, duration of response (DOR), time to Tx failure, time to next antimyeloma Tx, health-related quality of life, and safety. With a data cutoff of May 24, 2013, the median follow-up was 37.0 months (mos).
Results: In pts who achieved ≥ VGPR, median PFS was significantly longer (NR) with continuous Rd compared with Rd18 (31.0 mos; HR = 0.46; P < 0.01) or MPT (34.7 mos; HR = 0.55; P < 001). Even greater benefit of continuous Rd was observed compared with Rd18 or MPT in pts who achieved CR, where the median PFS with continuous Rd was NR vs. 45.2 mos with Rd18 (HR = 0.29; P < 0.01) and 44.6 mos with MPT (HR = 0.28; P < 0.01) (Table 1). In the intent-to-treat population, duration of response (DOR) was 35 mos with continuous Rd, which was significantly longer of almost a year vs. Rd18 (22.1 mos; HR = 0.60; P < 0.01) or MPT (22.3; HR = 0.63; P < 0.01). Importantly, the DOR was significantly longer with continuous Rd vs. Rd18 or MPT across all response categories, including pts with CR. Median duration of CR was NR vs. 43.6 mos in pts receiving continuous Rd vs. Rd18 (HR = 0.29; P < 0.01); ≥ VGPR, NR vs. 29.9 mos (HR = 0.46; P < 0.01); and ≥ PR, 35 mos vs. 22.1 mos (HR = 0.60; P < 0.01). In pts who achieved CR, 88% were disease-free after 36 mos with continuous Rd vs. 55% Rd18 and 54% MPT. In terms of OS, only interim data on continuous Rd vs. Rd18 or MPT on depth of response in the subgroups is presented in table 1.
Conclusions: The DOR was significantly longer (12-18 mos) as was PFS in pts treated with continuous Rd vs. Rd18 or MPT regardless of the depth of response. The benefits of continuous Rd were more pronounced in pts who achieved a greater depth of response (≥ VGPR). These data suggest that continuing Tx after best response may further help in controlling the disease and delaying PD, especially in pts achieving CR. Longer follow-up may be needed to determine the impact of response quality on OS in pts receiving continuous Tx.
PFS, DOR, and OS in pts with NDMM
| . | CR (n = 209) . | ≥ VGPR (n = 618) . | ≥ PR (n = 1140) . | ≤ SD (n = 483) . | ITT pts (N = 1623) . |
|---|---|---|---|---|---|
| Median PFS (mos) | |||||
| Rd | NR | NR | 37.7 | 3.7 | 27.4 |
| Rd18 | 45.2 | 31.0 | 24.0 | 4.6 | 21.3 |
| MPT | 44.6 | 34.7 | 26.3 | 4.9 | 21.8 |
| PFS, HR (95% CI); P-value | |||||
| Rd vs. MPT | 0.28 (0.13–0.61); P < 0.01 | 0.55 (0.40–0.76); P < 0.01 | 0.67 (0.55–0.82); P < 0.01 | 1.60 (1.22–2.11); P < 0.01 | 0.68 (0.56–0.83); P < 0.01 |
| Rd vs. Rd18 | 0.29 (0.15–0.58); P < 0.01 | 0.46 (0.34–0.60); P < 0.01 | 0.60 (0.49–0.72); P < 0.01 | 1.10 (0.82–1.48); P = 0.53 | 0.68 (0.55–0.83); P < 0.01 |
| Median DOR (mos) | |||||
| Rd | NR | NR | 35.0 | – | 35.0 |
| Rd18 | 43.6 | 29.9 | 22.1 | – | 22.1 |
| MPT | 41.9 | 31.8 | 22.3 | – | 22.3 |
| DOR, HR (95% CI); P-value | |||||
| Rd vs. MPT | 0.27 (0.13–0.59); P < 0.01 | 0.54 (0.39–0.74); P < 0.01 | 0.63 (0.51–0.76); P < 0.01 | – | 0.63 (0.51–0.76); P < 0.01 |
| Rd vs. Rd18 | 0.29 (0.15–0.59); P < 0.01 | 0.46 (0.35–0.61); P < 0.01 | 0.60 (0.50–0.72); P < 0.01 | – | 0.60 (0.50–0.72); P < 0.01 |
| Median OS (mos) | |||||
| Rd | NR | NR | 55.1 | 33.2 | 55.1 |
| Rd18 | NR | NR | NR | 26.8 | 53.6 |
| MPT | NR | NR | NR | 31.6 | 48.2 |
| OS, HR (95% CI); P-value | |||||
| Rd vs. MPT | 0.59 (0.23–1.49); P = 0.26 | 0.77 (0.50–1.180; P = 0.23 | 0.85 (0.64–1.11); P = 0.23 | 0.98 (0.72–1.33); P = 0.89 | 0.78 (0.64–0.96); P < 0.02 |
| Rd vs. Rd18 | 0.84 (0.34–2.07); P = 0.71 | 0.82 (0.56–1.22); P = 0.33 | 0.90 (0.69–1.17); P = 0.45 | 0.97 (0.70–1.35); P = 0.85 | 0.90 (0.73–1.10); P =0.31 |
| CI, confidence interval; ITT, intent-to-treat. | |||||
| . | CR (n = 209) . | ≥ VGPR (n = 618) . | ≥ PR (n = 1140) . | ≤ SD (n = 483) . | ITT pts (N = 1623) . |
|---|---|---|---|---|---|
| Median PFS (mos) | |||||
| Rd | NR | NR | 37.7 | 3.7 | 27.4 |
| Rd18 | 45.2 | 31.0 | 24.0 | 4.6 | 21.3 |
| MPT | 44.6 | 34.7 | 26.3 | 4.9 | 21.8 |
| PFS, HR (95% CI); P-value | |||||
| Rd vs. MPT | 0.28 (0.13–0.61); P < 0.01 | 0.55 (0.40–0.76); P < 0.01 | 0.67 (0.55–0.82); P < 0.01 | 1.60 (1.22–2.11); P < 0.01 | 0.68 (0.56–0.83); P < 0.01 |
| Rd vs. Rd18 | 0.29 (0.15–0.58); P < 0.01 | 0.46 (0.34–0.60); P < 0.01 | 0.60 (0.49–0.72); P < 0.01 | 1.10 (0.82–1.48); P = 0.53 | 0.68 (0.55–0.83); P < 0.01 |
| Median DOR (mos) | |||||
| Rd | NR | NR | 35.0 | – | 35.0 |
| Rd18 | 43.6 | 29.9 | 22.1 | – | 22.1 |
| MPT | 41.9 | 31.8 | 22.3 | – | 22.3 |
| DOR, HR (95% CI); P-value | |||||
| Rd vs. MPT | 0.27 (0.13–0.59); P < 0.01 | 0.54 (0.39–0.74); P < 0.01 | 0.63 (0.51–0.76); P < 0.01 | – | 0.63 (0.51–0.76); P < 0.01 |
| Rd vs. Rd18 | 0.29 (0.15–0.59); P < 0.01 | 0.46 (0.35–0.61); P < 0.01 | 0.60 (0.50–0.72); P < 0.01 | – | 0.60 (0.50–0.72); P < 0.01 |
| Median OS (mos) | |||||
| Rd | NR | NR | 55.1 | 33.2 | 55.1 |
| Rd18 | NR | NR | NR | 26.8 | 53.6 |
| MPT | NR | NR | NR | 31.6 | 48.2 |
| OS, HR (95% CI); P-value | |||||
| Rd vs. MPT | 0.59 (0.23–1.49); P = 0.26 | 0.77 (0.50–1.180; P = 0.23 | 0.85 (0.64–1.11); P = 0.23 | 0.98 (0.72–1.33); P = 0.89 | 0.78 (0.64–0.96); P < 0.02 |
| Rd vs. Rd18 | 0.84 (0.34–2.07); P = 0.71 | 0.82 (0.56–1.22); P = 0.33 | 0.90 (0.69–1.17); P = 0.45 | 0.97 (0.70–1.35); P = 0.85 | 0.90 (0.73–1.10); P =0.31 |
| CI, confidence interval; ITT, intent-to-treat. | |||||
Bahlis:Celgene: Honoraria, Research Funding. Off Label Use: Lenalidomide used in newly diagnosed multiple myeloma patients. Stoppa:Celgene, Janssen: Honoraria. Decaux:Celgene and Janssen-Cilag : Consultancy, Honoraria. Marit:Celgene, Janssen: Congress expenses Other. Demuynck:Janssen-Cilag: Honoraria. Ervin-Haynes:Celgene: Employment. Leupin:Celgene: Employment. Marek:Celgene: Employment, Equity Ownership. Chen:Celgene: Employment. Facon:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.
Author notes
Asterisk with author names denotes non-ASH members.
