Long-term follow-up of Total Therapy IV: a phase 3 clinical trial for standard-risk multiple myeloma

TO THE EDITOR:

Multiple myeloma (MM), historically perceived as an incurable malignancy, now demonstrates excellent long-term survival.^1-3 This paradigm shift reflects the ongoing progress in the understanding of the disease's molecular complexities and the development of innovative treatment modalities, including the introduction of immunomodulatory drugs, proteasome inhibitors, anti-CD38 monoclonal antibodies, and high-dose chemotherapy followed by autologous hematopoietic stem cell transplantation (HSCT).^4-6 The absence of robust long-term follow-up data in phase 3 trials for MM underscores a critical gap in our understanding of the durability of treatment responses and the eventual outcomes for patients.⁷ 

Within our Total Therapy (TT) program, the strategic application of all MM-active agents upfront, aimed at diminishing the development or survival of drug-resistant subclones, has resulted in significant progress.^8-11 Initial results of the randomized TT IV phase 3 clinical trial after a median follow-up of 4.5 years were previously published.¹² This report presents the analysis of the longest-term follow-up of any phase 3 clinical trial in MM by focusing on clinical outcomes in patients classified as having low-risk MM based on their gene-expression profile that were enrolled in the TT IV trial (NCT00734877).

The protocol, treatment details along with consort diagram of the trial, has been described previously (supplemental).¹² After enrolling and randomizing 289 patients, the Data Safety Monitoring Board recommended closing the long-term TT IV (L-TT IV) arm due to the absence of a reduction in toxicity compared with short-term TT IV (S-TT IV). A total of 94 patients were enrolled to S-TT IV without randomization. Detailed methods, end points, and statistical analysis are summarized in the supplemental.

The study was approved by the University of Arkansas for Medical Sciences Institutional Review Board.

The study enrolled a total of 380 patients, 238 of which were enrolled into S-TT IV and 142 of which were enrolled into L-TT IV. Patient characteristics are summarized in Table 1. The median follow-up for the S-TT IV arm was 11.1 years (interquartile range [IQR], 9.2-13.0), whereas the L-TT IV arm had a median follow-up of 13.1 years (IQR, 11.6-13.9). The overall median follow-up was 11.8 years (IQR, 10.1-13.4). No difference in adverse events was found between both arms apart from lower grade 3/4 infection in patients who were enrolled in S-TT IV.

The median overall survival (OS) was 13.3 years (95% confidence interval [CI], 12.5 years to not reached [NR]). The 1-, 3-, 5-, and 10-year OS was 96%, 89%, 80%, and 61%, respectively. There was no significant OS difference between the L-TT IV and S-TT IV arms (P = .5), the medians (95% CI; 10-year percentages) of which were 12.8 years (10.4 years to NR; 59%) and 13.3 years (12.6 years to NR; 63%), respectively (Figure 1). The hazard ratio (HR) for the L-TT IV arm was 1.12 (95% CI, 0.81-1.53; P = .49) compared with S-TT IV. In a 6-month landmark from HSCT multivariate Cox regression (supplemental Table 1), there was a significant reduction risk of death (47%) among patients who underwent tandem vs single autologous HSCT (HR, 0.53; 95% CI, 0.35-0.80; P = .003). Older age was associated with slightly worse OS (HR, 1.03; 95% CI, 1.00-1.05; P = .02), and baseline hypercalcemia was associated with worse OS (HR, 1.12; 95% CI, 1.01-1.22; P = .033).

The median progression-free survival (PFS) was 7 years (95% CI, 6.0-8.8 years). The 1-, 3-, 5-, and 10-year PFS were 91%, 77%, 62%, and 41%, respectively. There was no difference in PFS between L-TT IV and S-TT IV arms (P = .2), the medians (95% CI; 10-year percentages) of which were 6 years (5.2-8.4 years; 37%) and 7.7 years (6.2-10.2 years; 43%), respectively (Figure 1). The HR for the L-TT IV arm was 1.20 (95% CI, 0.70-1.80; P = .64) compared with S-TT IV. On multivariable analysis, there was no significant PFS difference in patients who underwent tandem vs single autologous HSCT, the HR of which was 0.76 (95% CI, 0.5-1.16; P = .203) (supplemental Table 2).

Because 94 patients were enrolled to S-TT IV without randomization, we summarized their baseline characteristics, OS, and PFS in supplemental Table 3 and supplemental Figures 1 and 2.

Data on measurable (or minimal) residual disease (MRD) are limited because it was introduced in 2012 after the initiation of the trial. Details on MRD testing results are provided in the supplemental. Sustained MRD negativity is defined as 3 consecutive negative test results with a minimum of 2 million events evaluated after HSCT. Sustained MRD negativity was achieved in 217 patients (68%) with no statistical difference between S-TT IV and L-TT IV.

A total of 71 malignancies were reported on patients at data cutoff (supplemental Table 5). In addition, 11 patients (3%) developed >1 malignancy. The most common reported malignancy was myelodysplastic syndrome (n = 17, 4%) and acute myeloid leukemia (n = 11, 3%). The cumulative incidence at 3, 5, 10, and 12 years of developing secondary solid or hematological malignancy was not different between S-TT IV and L-TT IV (supplemental Figures 4 and 5; supplemental Tables 6 and 7). The 10-year cumulative incidence of developing any secondary hematological malignancy was 7.6% (95% CI, 3.9-13) and 6.4% (95% CI, 3.7-10) for L-TT IV and S-TT IV, respectively. Tandem HSCT was associated with a tendency toward decreased risk of secondary hematological malignancies when compared with single HSCT (HR, 0.66; 95% CI, 0.29-1.51), but the 34% decrease was not statistically significant (P = .3) (supplemental Figure 6; supplemental Table 8). However, tandem HSCT was associated with a 51% lower risk of secondary solid malignancy (HR, 0.49; 95% CI, 0.25-0.97) that did attain statistical significance (P = .041) (supplemental Figure 7; supplemental Table 9).

Our study presents the longest follow-up data from any phase 3 clinical trial in MM, offering critical insights into the durability of treatment responses and overall patient outcomes with limited-duration therapy. The study's median OS of 13.3 years highlights the remarkable progress in MM treatment. Notably, the 10-year OS rate stands at 61%, whereas the 10-year PFS rate is 41%. These findings underscore the potential long-term benefits of fixed-duration, triplet-based treatment as demonstrated in the TT IV protocol.

We believe that this evidence supports the consideration of finite-duration treatment in all patients with standard-risk MM. Although further studies could explore shorter treatment durations (<3 years of bortezomib, lenalidomide, and dexamethasone [VRD]) and/or treatments based on MRD negativity, our study demonstrates that a fixed-duration treatment involving 1 to 2 autologous HSCT and 3 years of VRD leads to excellent long-term outcomes. Stopping treatment based on MRD status is possible as found in the MASTER study.¹³ Among the patients who achieved MRD negativity, 71% were able to cease therapy. The cumulative incidence of progression or MRD resurgence at 12 months was relatively low at 6.4%. This suggests that treatment cessation based on MRD status is feasible, particularly for patients with no high-risk features and who achieve MRD negativity earlier in their treatment course.

Our study used fixed-duration dual-maintenance/extended therapy for patients with low-risk MM. Notably, with fixed-duration therapy of <4 years, 41% of patients remained disease free and off therapy. This suggests that a significant percentage of patients who undergo intensive, fixed-duration therapy may not experience relapse even after a 10-year follow-up.

There was no significant difference in secondary malignancies between the S-TT IV and L-TT IV arms. Single-dose melphalan at 200 mg/m² remains the standard conditioning regimen, and tandem HSCT was not associated with an increased incidence of secondary hematological malignancies. Although baseline positron emission tomography focal lesions and abnormal metaphase cytogenetics predicted poor OS at 4.5 years, these factors did not predict long-term survival at 12 years, underscoring the importance of extended follow-up.

Given that our study began in 2008, the use of upfront anti-CD38 therapy was not yet approved. However, with the introduction of upfront anti-CD38 therapy, outcomes are expected to improve, as evidenced by more recent studies such as the PERSEUS trial.¹⁴ The use of quad-based induction is used more often given the ease of administration; however, no direct comparison between quad-based therapy and our induction regimen was used in TT IV. Furthermore, we have incorporated daratumumab in TT VII (ClinicalTrials.gov identifier: NCT03004287), and the results of this study will be reported in future.

Our study contributes to the growing body of evidence that demonstrates significant advancements in the management of MM and consequent improvements in patient outcomes. Fixed-duration therapy in low-risk MM is both feasible and effective, leading to excellent long-term outcomes.

Acknowledgments: The authors sincerely acknowledge the patients and their families who participated in the TT IV study.

TT IV was supported by National Cancer Institute, National Institutes of Health Program Project grant CA55819.

Contribution: S.A.H., C.S., S.T., B.B., M.Z., and F.v.R. contributed to the conception and design of the study; S.A.H., C.S., S.T., C.B., R.S., S.P., D.A., G.T., J.S. Jr, F.Z., J.S., B.B., M.Z., and F.v.R. made provision for study materials or patients; S.A.H., C.B., R.S., and S.P. performed collection and assembly of data; and all authors were involved in data analysis and interpretation, manuscript writing, final approval of manuscript, and were accountable for all aspects of the work.

Conflict-of-interest disclosure: S.A.H. reports consulting fees from Jansen, Sanofi, and Pfizer. The remaining authors declare no competing financial interests.

Correspondence: Samer Al Hadidi, Myeloma Institute, Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, 449 Jack Stephens Dr, Little Rock, AR 72205; email: salhadidi@uams.edu.