Improvement in long-term outcomes with successive Total Therapy trials for multiple myeloma: are patients now being cured?

Abstract

The concept of applying all active therapeutic agents in Total Therapy (TT) clinical trials for newly diagnosed multiple myeloma was pursued with the intent of developing curative treatment. The results of TT1 (n=231), TT2 (n=668) without or with thalidomide and TT3 with added bortezomib (n=303) have been reported. An update with median follow-up times of 17.1, 8.7 and 5.5 years, respectively, is provided. Conditional overall survival (OS) analysis from a 4-year landmark was applied to account for earlier protocol failure owing to disease aggressiveness and toxicities. Cumulative relative survival was computed in the context of age- and gender-matched US population, and interval-specific relative survival ratios were estimated to determine times to normal survival expectation. Based on Cox model-adjusted statistics, OS, progression-free survival and complete-response duration all improved with the transitions from TT1 to TT2 to TT3; improvement was also evident from time-to-progression estimates, 4-year conditional survival data and cumulative relative survival. Interval-specific relative survival normalized progressively sooner, reaching near-normal levels with TT3 in patients who attained complete response. Thus, a strategy using all myeloma-effective agents up-front seems effective at preventing, in progressively larger patient cohorts over time, the outgrowth of resistant tumor cells that account for ongoing relapses.

Figure 1

Kaplan–Meier plots of OS (a), PFS (b) and CR duration (c) for TT trials. Significant improvements were observed in OS, PFS and CR duration with the transitions from earlier trials to later trials that incorporated new agents, greater intensity of induction therapy and consolidation therapy after transplantation. This was especially apparent in the Cox model-derived comparisons adjusted for baseline prognostic factors. Black, TT1; red, TT2 − Thal; blue, TT2 + Thal; and green, TT3. *Model-adjusted P-value based on Cox regression model including terms for TT protocol, age, β-2microglobulin >5.5 mg/l, lactate dehydrogenease ≥190 U/l and the presence of CA.

Figure 2

Cumulative incidence of progression or relapse for all patients (a) and for those who attained CR (b). (a) Cumulative incidences of relapse or progression consistently decreased over successive protocols. (b) Cumulative incidences of relapse following CR (for the subset of patients who achieved CR) show progressive improvements in outcome with transitions from early to later trials. Significant differences were observed with both log-rank statistics and Cox model-derived comparisons adjusted for baseline prognostic factors. Black, TT1; red, TT2 − Thal; blue, TT2 + Thal; and green, TT3. *Model-adjusted P-value based on Cox regression model including terms for TT protocol, age, β-2microglobulin >5.5 mg/l, lactate dehydrogenease ≥190 U/l and the presence of CA.

Figure 3

Conditional survival outcomes from 4-year landmark in TT trials, shown for OS (a), PFS (b) and CR duration (c). Significant improvements in 4-year conditional survival were noted for all three endpoints with successive TT trials, especially when comparisons were adjusted for baseline prognostic factors. Black, TT1; red, TT2 − Thal; blue, TT2 + Thal; and green, TT3. *Model-adjusted P-value based on Cox regression model including terms for TT protocol, β-2microglobulin >5.5 mg/l and the presence of CA.

Figure 4

Improvements in cumulative relative survival were observed in successive TT trials, whether considered from onset of therapy (a) or from onset of CR (b). OS was adjusted for the expected survival of the US population, stratified by gender and age at registration. Successive improvements were noted when comparing TT1 with TT2 and with TT3. No difference was detected between TT2 − Thal and TT2 + Thal. Black, TT1; blue, TT2 − Thal; red, TT2 + Thal; and green, TT3.

Figure 5

IRS ratios from the start of therapy for all patients (a) or from the onset of CR for the subset of patients who attained CR (b). OS, adjusted for the expected survival of the US population, stratified by gender and age at registration, was calculated over 1-year intervals. With the transitions from TT1 to TT2 and TT3 trials, IRS ratios were successively higher from the outset, and improvements toward normal occurred earlier, whether examined for all patients or for those who attained CR. Black, TT1; blue, TT2 − Thal; red, TT2 + Thal; and green, TT3. (95% Confidence intervals provided in Supplementary Tables 2A–B).