Clinical outcome from initiation of TT2, overall and by treatment arm and in relationship to TT1
Patient characteristics were similar between the two arms of the study and, in comparison to TT1, patients on TT2 as a group were older and had higher frequencies of some adverse variables [elevations of lactate dehydrogenase (LDH) and C-reactive protein (CRP), IgA isotype] and of some favourable features (higher haemoglobin and albumin levels) (). Patients had similar frequencies of CA. depicts the cumulative progression of patients through the protocol phases of TT1 and TT2 (both arms combined as there was no difference between them). Results showed more rapid progression through the successive protocol steps with TT2 than TT1.
Characteristics of patients enrolled in total therapy 2 (TT 2) according to protocol arm [with or without thalidomide (THAL)] and in total therapy 1 (TT1).
Cumulative proportions of patients completing successive treatment steps of total therapy 1 (TT1) and total therapy 2 (TT2). Abbreviations: Tx1 (1st transplant), Tx2 (2nd transplant).
With TT2, the median follow-up of the 416 currently living patients was 5 years; and with TT1, the median follow-up of the 55 live patients was 12 years. The median durations of OS and EFS for TT2 were 8.0 and 4.8 years, respectively, compared to 5.7 and 2.6 years in the case of TT1 (). Of the 668 subjects initially enrolled in TT2, 252 have died (MM progression, 207; treatment-related toxicities, 45) and 370 have experienced an event (relapse/progression, 118; death due to MM, 207, and other causes, 45); the corresponding data for TT1 are 176 deaths (MM progression, 160; treatment-related, 16) and 204 events (relapse/progression, 28; death due to MM, 160, and other causes, 16).
Fig 3 Kaplan–Meier plots of clinical outcomes with total therapy 2 (TT2) and total therapy 1 (TT1). (A) The median durations of overall survival (OS) and event-free survival (EFS) for all 668 patients enrolled in TT2 were 8.0 and 4.8 years respectively. (more ...)
The Kaplan–Meier plots portray outcomes for the two arms of TT2 and for TT1, with statistical differences annotated between TT1 and TT2, both combined and by study arm. The addition of THAL in TT2 raised the CR frequency to 60% from 40% noted for the control arm, which was identical to results with TT1 (P = 0.001) (). CR duration from onset of CR was similar for both arms of TT2 and superior to TT1 (). In the case of EFS, TT2 plus THAL was superior to the control arm, which, in turn, exceeded results obtained with TT1 (). A trend was observed for longer OS on the THAL arm versus control arm of TT2 (diverging at 5 years), both of which were superior to TT1 (). The postrelapse survival on TT2 tended to be longer, at a median of 2.7 years versus 1.6 years on the control versus THAL arm (P = 0.06) (). Treatment-related mortality (TRM) was similar in the two studies, reaching from 5% to 6% among patients younger than 65 years and approximately 10% in the older cohort ().
Given the dominant adverse impact of CA in both TT1 and TT2, outcomes were compared among patients with and without CA. EFS and OS were superior with TT2 (both arms) among the patients presenting without CA (). The CA subgroup benefited from the addition of THAL in TT2, whereas outcomes were similar between TT1 and the control arm of TT2 (see ).
Multivariate analysis of pretreatment prognostic factor and of therapy
lists, for outcomes on TT2, the independently significant prognostic factors, along with treatment arms. The presence of CA was an adverse feature for all three endpoints; elevation of LDH conferred poor OS and EFS; and increased creatinine and low albumin predicted for shorter OS. Randomization to THAL imparted longer EFS but not OS or CR duration. Relative to TT1, TT2 was superior with regard to all outcome endpoints; CA affected all three endpoints adversely, while elevated LDH levels were associated with shorter OS and EFS (). These results pertained also when outcomes were compared between the individual arms of TT2 and TT1 (data not shown).
Multivariate analysis of clinical outcomes with total therapy 2 (TT2) by protocol arm.
Multivariate analysis of clinical outcome adjusting for treatment (TT2 + THAL, TT2 − THAL, TT 1).
Post-transplant survival in TT2 related to chemotherapy or dexamethasone consolidation and in relationship to TT1
Post-transplant OS and EFS in TT2 were similar, regardless of the consolidation chemotherapy strategy employed (originally randomization between DCEP every 3 months for four cycles and DCEP alternating with CAD every 6 weeks for eight cycles; after the 109th patient enrolled, because of similar outcomes between the two consolidation arms, subsequent patients were treated with D-PACE every 3 months for four cycles) (data not shown). There was an additional provision for non-cytotoxic dexamethasone (DEX) to be given to patients either not having recovered a minimum platelet level of 100 × 109/l at 3 months from last transplant or not having responded adequately to DCEP induction; no difference in survival was noted between these two patient groups (not shown). For the control arm of TT2, consolidation chemotherapy was superior to DEX in the CA subgroup (), whereas such difference was not apparent for patients treated on the experimental arm of TT2 ().
Fig 4 Overall survival post-transplant of patients treated with total therapy 2 (TT2) and total therapy 1 (TT1). (A) For patients treated on the control arm of TT2, overall survival from post-transplant consolidation was similar among patients without cytogenetic (more ...)
Post-transplant OS was then examined in TT2 versus TT1 in relationship to CA as the major adverse prognostic variable in both studies. Relative to TT1, patients without CA enjoyed superior OS on both TT2 arms (); in the presence of CA, those randomized to THAL fared better than their counterparts treated on the control arm of TT2 or with TT1 (). Collectively, the results presented in suggest a role for THAL in MM with CA, as was also noted for both EFS and OS when examined from initiation of protocol therapy (see ).
Analysis of TT2 outcomes by pretreatment prognostic factors including GEP
As summarized in , GEP-derived high-risk score (≥0.66) added independently to the prognostic models for OS, EFS and CR duration, displacing CA from the EFS model, whereas LDH and creatinine were retained for both OS and EFS. These findings pertained to both arms of TT2 (data not shown). Thus, the 4-year OS, EFS and CR estimates were 80%, 60% and 60%, respectively, among the 87% of patients with a low-risk score as opposed to 30%, 20% and 30%, respectively, in the 13% with high-risk score (). No significant differences were observed in OS and CR duration within GEP-defined risk groups by treatment arm whereas, for EFS, THAL benefited the low-risk subgroup (data not shown).
Multivariate analysis of clinical outcomes on total therapy 2 (TT2) (both arms) according to pretreatment variables inclusive of gene expression profiling (GEP)-defined risk category.
Fig 5 Superior clinical outcomes among patients receiving total therapy 2 (TT2) with gene expression profiling (GEP)-defined standard-risk versus high-risk myeloma. (A) Overall survival was highly superior in the low- versus high-risk group. (B) Event-free (more ...)
Relapse rate in TT2 and TT1 in relationship to phases of treatment
We examined cumulative relapse frequencies after first and second transplant and maintenance phases (). Among patients without CA, relapses occurred earlier and more frequently after both first and second transplants in TT1 compared with TT2 (), whereas this benefit was less pronounced in the case of CA due to earlier onset and higher rates of relapse on both trials (). Once in maintenance, THAL effectively reduced the relapse rate in comparison with the control arm of TT2, which, in turn, was similar to the relapse rate after TT1.
Fig 6 Cumulative proportions of patients relapsing in the 12 months after various treatment steps in total therapy 2 (TT2) with thalidomide (TT2 + THAL) versus TT2 without thalidomide (TT2 − THAL) versus total therapy 1 (TT1). Additional abbreviations (more ...)
Pair-mate analysis of clinical outcomes of patients treated with TT1, TT2 − THAL and TT2 + THAL
With TT1, the presence of CA and elevations of C-reactive protein (CRP ≥8.0 mg/l) and creatinine (≥176.8 μmol/l) were the three key adverse variables for OS. We identified 204 patients each in TT1 and the two arms of TT2 who were closely matched for these three variables. A trend was apparent for OS to be superior with TT2 plus THAL versus TT1, while there was no significant difference between the two arms of TT2 (). EFS and CR duration plots differed significantly when examined in pair-wise comparisons, so that TT2 plus THAL was superior to TT2 without THAL, which was superior to TT1 in terms of EFS () and CR duration ().
Fig 7 Pair-mate analysis of patients treated with total therapy 2 (TT2) and total therapy 1 (TT1). Matching was done on cytogenetic abnormalities (CA), CRP (>8 mg/l) and creatinine (≥176.8 μmol/l), found to be the leading adverse variables (more ...)