KM plots over time of OS, EFS, and CRD were completely superimposable, indicating absence of time-dependent differences in the characteristics of successively enrolled patients (). Indeed, there was no difference during the time of trial accrual from year 1 to year 6 in the frequency of baseline laboratory parameters of recognized prognostic significance such as elevated serum levels of beta-2-microgobulin (B2M; ≥ 3.5 or > 5.5 mg/L), C-reactive protein (≥ 4.0 or ≥ 8 mg/L), lactate dehydrogenase (LDH; ≥ 190 U/L) and creatinine (≥ 2.0 mg/dL); low levels of albumin (< 3.5 g/dL) and hemoglobin (< 10 g/dL); and, importantly, the presence of CA and GEP-defined high-risk designation (data not shown). Reiterative KM plots according to potentially important variables are portrayed in , covering years 6, 8, and 10 from enrollment or relapse. The presence of CA conferred inferior OS throughout (A), which also pertained to EFS and CRD (not shown). Although discontinued due to toxicity in approximately 80% of patients within 2 years from starting protocol therapy,7
thalidomide's benefit became manifest at a significant level of P
< .05 only after 7 years for EFS (not shown) and 10 years for OS (B). The higher CR frequency on the experimental arm did not translate into longer CRD (P
= .15; data not shown), thus not explaining the late survival benefit of patients randomly assigned to thalidomide. According to statistical analyses that tested for potential interaction, thalidomide's preferential benefit in CA-type myeloma17
was confirmed and became apparent for EFS in year 8 (not shown) and for OS in year 10 (C). The initially observed shorter postrelapse survival (PRS) in case of random assignment to thalidomide7
disappeared with longer follow-up (D), so that by year 10, PRS curves had crossed in favor of the thalidomide arm. Given thalidomide's preferential benefit in CA-type myeloma, PRS was also examined in the context of baseline CA status. While initially appearing superior in case of random assignment to the control arm, PRS curves for the thalidomide arm crossed those for the control arm by year 10 independent of CA status (E). The similarity in PRS between the two study arms could not be attributed to differences in access to or utilization of lenalidomide and bortezomib as primary salvage therapies, which were employed in 43% and 9% of patients treated on the control arm and in 49% and 8% of those randomly assigned to thalidomide.
Fig 1. Serial Kaplan-Meier plots of overall survival (A), event-free survival (B) and complete response (CR) duration (C) from various times of trial enrollment. The curves are superimposable, suggesting that patients' characteristics and quality of care provided (more ...)
Fig 2. Survival plots depicted as a function of increasing time intervals to the present time (left column, year 6; middle column, year 8; right column, year 10). (A) The presence of cytogenetic abnormalities (CA) consistently affected survival adversely. (B) (more ...)
The results of serial multivariate analyses of baseline variables affecting OS and EFS are depicted in . In the larger patient set without GEP data, low serum albumin levels, elevated LDH and B2M concentrations, and the presence of CA exerted fairly consistent adverse effects on both OS and EFS (A). Thalidomide's favorable impact was detectable for EFS at year 7 and for OS not until year 10. Hazard ratio values for albumin and LDH, but not CA, decreased over time. In addition, when GEP data were considered, high-risk designation (13% of patients) dominated both OS and EFS models, whereas the deleterious roles of CA and LDH were less pronounced (B). High B2M essentially failed to affect clinical outcomes, while serum creatinine levels of 2 mg/dL and greater imparted poor outcomes only early on. Random assignment to thalidomide was a favorable feature for EFS but not OS.
Fig 3. Display of hazard ratio (HR) values of baseline prognostic variables on overall survival (OS) and event-free survival (EFS) as a function of years since enrollment. The HRs and 95% CIs are based on a multivariate Cox regression. An X indicates that the (more ...)
Cumulative thalidomide dosing, whether considered across all treatment phases or separately by induction, peritransplant, consolidation, and maintenance, did not affect OS, EFS, or CRD, regardless of CA status (data not shown).