Abstract
Background: In the pivotal FIRST trial, a randomized, international, multicenter phase 3 study, continuous Rd compared with melphalan-prednisone-thalidomide (MPT) improved progression-free survival (PFS) which was the primary endpoint (HR = 0.72; P < 0.01). The interim overall survival (OS) analysis showed a 22% reduction in risk of death with continuous Rd vs. MPT (HR = 0.78; P = 0.02) (Facon, Blood 2013). This analysis evaluates outcomes based on age, which was a stratification parameter, and compared pts aged ≤ 75 yrs and > 75 yrs.
Methods: Pts with NDMM were randomized to continuous Rd until progressive disease (PD) (N = 535); 18 cycles (72 weeks [wks]) of Rd (Rd18; N = 541); or 12 cycles (72 wks) of MPT (N = 547). Starting doses were reduced in pts aged > 75 yrs: dexamethasone (20 vs. 40 mg), melphalan (0.20 vs. 0.25 mg/kg), and thalidomide (100 vs 200 mg). The primary endpoint was PFS (continuous Rd vs. MPT) and the secondary endpoint were OS, overall response rate, time to response, duration of response, time to Tx failure, time to 2nd AMT, health-related quality of life, safety.
Results: The proportion of pts aged > 75 yrs was > 34% across treatment (Tx) arms. In pts ≤ 75 yrs, 37% had ISS stage III vs. 51% in > 75 yrs. ECOG score ≥ 1 was observed in 74% and 69% of pts aged > 75 and ≤ 75 yrs, respectively. Severe renal impairment (CrCl < 30 mL/min) was observed in 14% of pts > 75 vs. 7% in ≤ 75 yrs. PFS and OS outcomes favored continuous Rd over MPT in both age groups. With a median follow-up of 37 months (mos), PFS was 27.4 mos in continuous Rd pts vs. 21.8 mos in MPT pts aged ≤ 75 yrs (HR = 0.68; P < 0.001); a trend for improved PFS was also seen for pts aged > 75 yrs (HR = 0.81; P = 0.11) (Table 1). PFS for continuous Rd vs. Rd18 pts was also increased in both age groups (HR = 0.68; P < 0.001 and HR = 0.75; P = 0.03, respectively). Response rates were consistently higher with continuous Rd vs. MPT in pts aged ≤ 75 yrs (77% vs. 66%; P < 0.001) and > 75 yrs (71% vs. 55%; P < 0.001). Duration of response with continuous Rd was longer vs. MPT in pts aged ≤ 75 yrs (40 vs. 22 mos) and pts > 75 yrs (31 vs. 24 mos). The interim analysis of OS showed an improved trend for continuous Rd vs. MPT in pts aged ≤ 75 yrs (HR = 0.77; P = 0.06) and > 75 yrs (HR = 0.80; P= 0.16). Grade 3–4 adverse events (AEs) in ≥ 10% of pts were similar across age subgroups (Table 2). Tx discontinuation due to AEs was comparable across the Tx groups and independent of age.
Conclusions:Regardless of age (≤ 75 vs. > 75 yrs), continuous Rd was effective, increased PFS and interim OS, and was generally well tolerated vs. MPT in NDMM pts. Duration of response was improved with continuous Rd vs. MPT and Rd18, irrespective of age, and with a more profound benefit observed in younger pts. Continuous Rd represents a new clinical option and standard of care for these pts in the first-line setting.
PFS, OS and Response
| . | Aged ≤ 75 yrs . | Aged > 75 yrs . | All pts . | ||||||
|---|---|---|---|---|---|---|---|---|---|
| ITT population . | Continuous Rd (n = 349) . | Rd18 (n = 348) . | MPT (n = 359) . | Continuous Rd (n = 186) . | Rd18 (n = 193) . | MPT (n = 188) . | Continuous Rd (n = 535) . | Rd18 (n = 541) . | MPT (n = 547) . |
| Median PFS, mos | 27.4 | 21.3 | 21.8 | 21.2 | 19.4 | 19.2 | 25.5 | 20.7 | 21.2 |
| PFS HR (95% CI); P-value | |||||||||
| Continuous Rd vs. Rd18 | 0.68 (0.55–0.83); P < 0.01 | 0.75 (0.58–0.98); P = 0.03 | 0.70 (0.60–0.82); P < 0.01 | ||||||
| Continuous Rd vs. MPT | 0.68 (0.56–0.83); P < 0.01 | 0.81 (0.62–1.05); P = 0.11 | 0.72 (0.61–0.85); P < 0.01 | ||||||
| 4-yr OS, % | 66 | 61 | 58 | 47 | 47 | 39 | 59 | 56 | 51 |
| OS HR (95% CI); P-value | |||||||||
| Continuous Rd vs. Rd18 | 0.88 (0.67–1.16); P = 0.36 | 0.94 (0.69–1.29); P = 0.70 | 0.90 (0.73–1.10); P = 0.31 | ||||||
| Continuous Rd vs. MPT | 0.77 (0.59–1.01); P = 0.06 | 0.80 (0.59–1.09); P = 0.16 | 0.78 (0.64–0.96); P = 0.02 | ||||||
| Response rate (≥ PR), % | 77 | 77 | 66 | 71 | 66 | 55 | 75 | 73 | 62 |
| Duration of response (≥ PR), mos | 40 | 23 | 22 | 31 | 20 | 24 | 35 | 22 | 22 |
| . | Aged ≤ 75 yrs . | Aged > 75 yrs . | All pts . | ||||||
|---|---|---|---|---|---|---|---|---|---|
| ITT population . | Continuous Rd (n = 349) . | Rd18 (n = 348) . | MPT (n = 359) . | Continuous Rd (n = 186) . | Rd18 (n = 193) . | MPT (n = 188) . | Continuous Rd (n = 535) . | Rd18 (n = 541) . | MPT (n = 547) . |
| Median PFS, mos | 27.4 | 21.3 | 21.8 | 21.2 | 19.4 | 19.2 | 25.5 | 20.7 | 21.2 |
| PFS HR (95% CI); P-value | |||||||||
| Continuous Rd vs. Rd18 | 0.68 (0.55–0.83); P < 0.01 | 0.75 (0.58–0.98); P = 0.03 | 0.70 (0.60–0.82); P < 0.01 | ||||||
| Continuous Rd vs. MPT | 0.68 (0.56–0.83); P < 0.01 | 0.81 (0.62–1.05); P = 0.11 | 0.72 (0.61–0.85); P < 0.01 | ||||||
| 4-yr OS, % | 66 | 61 | 58 | 47 | 47 | 39 | 59 | 56 | 51 |
| OS HR (95% CI); P-value | |||||||||
| Continuous Rd vs. Rd18 | 0.88 (0.67–1.16); P = 0.36 | 0.94 (0.69–1.29); P = 0.70 | 0.90 (0.73–1.10); P = 0.31 | ||||||
| Continuous Rd vs. MPT | 0.77 (0.59–1.01); P = 0.06 | 0.80 (0.59–1.09); P = 0.16 | 0.78 (0.64–0.96); P = 0.02 | ||||||
| Response rate (≥ PR), % | 77 | 77 | 66 | 71 | 66 | 55 | 75 | 73 | 62 |
| Duration of response (≥ PR), mos | 40 | 23 | 22 | 31 | 20 | 24 | 35 | 22 | 22 |
CI, confidence interval; ITT, intent to treat; PR, partial response.
Grade 3–4 AEs Observed in ≥ 10% of Pts
| . | Aged ≤ 75 yrs . | Aged > 75 yrs . | ||||
|---|---|---|---|---|---|---|
| Safety population, % . | Continuous Rd (n = 347) . | Rd18 (n = 348) . | MPT (n = 357) . | Continuous Rd (n = 185) . | Rd18 (n = 192) . | MPT (n = 184) . |
| Neutropenia | 28 | 25 | 47 | 28 | 29 | 40 |
| Thrombocytopenia | 8 | 9 | 13 | 9 | 7 | 7 |
| Anemia | 18 | 12 | 20 | 19 | 23 | 17 |
| Leukopenia | 5 | 6 | 11 | 4 | 5 | 8 |
| Infections | 29 | 21 | 16 | 29 | 23 | 20 |
| DVT and/or PE | 10 | 6 | 8 | 7 | 8 | 4 |
| Peripheral sensory neuropathy | 1 | 1 | 10 | 1 | 0 | 8 |
| Tx discontinuation due to AEs | 28 | 18 | 28 | 32 | 25 | 30 |
| . | Aged ≤ 75 yrs . | Aged > 75 yrs . | ||||
|---|---|---|---|---|---|---|
| Safety population, % . | Continuous Rd (n = 347) . | Rd18 (n = 348) . | MPT (n = 357) . | Continuous Rd (n = 185) . | Rd18 (n = 192) . | MPT (n = 184) . |
| Neutropenia | 28 | 25 | 47 | 28 | 29 | 40 |
| Thrombocytopenia | 8 | 9 | 13 | 9 | 7 | 7 |
| Anemia | 18 | 12 | 20 | 19 | 23 | 17 |
| Leukopenia | 5 | 6 | 11 | 4 | 5 | 8 |
| Infections | 29 | 21 | 16 | 29 | 23 | 20 |
| DVT and/or PE | 10 | 6 | 8 | 7 | 8 | 4 |
| Peripheral sensory neuropathy | 1 | 1 | 10 | 1 | 0 | 8 |
| Tx discontinuation due to AEs | 28 | 18 | 28 | 32 | 25 | 30 |
DVT, deep-vein thrombosis; PE, pulmonary embolism.
Hulin:Celgene: Honoraria. Off Label Use: Lenalidomide used in newly diagnosed multiple myeloma patients. Facon:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Belch:Janssen, Celgene, Onyx: Honoraria. Petrucci:Celgene, Janssen-Cilag, Sanofi, Bristol-Myers Squibb: Honoraria. Dührsen:Celgene: Honoraria, Research Funding. Song:Celgene: Consultancy, Honoraria, Research Funding. Houck:Celgene: Employment. Chen:Celgene: Employment. Ervin-Haynes:Celgene: Employment.
Author notes
Asterisk with author names denotes non-ASH members.
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