Additional interventions following upfront autologous stem cell transplant in multiple myeloma did not further improve progression-free or overall survival over transplant alone in a multicenter study presented as a late-breaking abstract at the 2016 American Society of Hematology (ASH) Annual Meeting & Exposition.¹

The addition of lenalidomide (Revlimid)/bortezomib (Velcade)/dexamethasone (RVD) consolidation or a second autotransplant was not superior to a single autotransplant followed by lenalidomide maintenance in the treatment of newly diagnosed multiple myeloma. The results come from the largest randomized comparison of posttransplant approaches in myeloma in the United States.

In the era of thalidomide analogs and proteasome inhibitors used in the initial therapy for myeloma and the use of prolonged maintenance therapy with lenalidomide, posttransplant consolidation with cycles of RVD or a second transplant do not produce incremental progression-free survival benefit.

— Edward A. Stadtmauer, MD

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“In the era of thalidomide analogs and proteasome inhibitors used in the initial therapy for myeloma and the use of prolonged maintenance therapy with lenalidomide, posttransplant consolidation with cycles of RVD or a second transplant do not produce incremental progression-free survival benefit,” said principal investigator Edward A. Stadtmauer, MD, of the University of Pennsylvania in Philadelphia.

“These results are very important because they answer a question that has been ongoing and has not been studied in a head-to-head comparison. The conclusion of the largest randomized U.S. transplant trial, so far, is that the other interventions are not superior to initial melphalan therapy followed by a single autotransplant followed by lenalidomide maintenance.”

Lenalidomide maintenance after autologous hematopoietic cell transplant has improved progression-free and overall survival. However, the role of additional interventions after autologous transplant, such as tandem transplant or triple-therapy consolidation, remains to be determined. The study was designed to evaluate whether further interventions would be beneficial.

The hypothesis was that the use of novel agents (thalidomide [Thalomid] analogs and proteasome inhibitors) incorporated initially and as consolidation and long-term maintenance after high-dose melphalan and autologous hematopoietic cell transplant would improve survival over a second autologous transplant.

StaMINA Design

StaMINA was a phase III clinical trial of the Bone and Marrow Transplant Clinical Trials Network. It enrolled 758 transplant-eligible patients (24% classified as high-risk) ≤ 70 years old (median = 57) with symptomatic myeloma within 12 months of initiating therapy and without prior disease progression.

“Although we didn’t define the induction treatment, these patients were certainly treated in the era of novel agents,” he indicated. More than half the patients, for example, had received RVD induction.

Patients were randomly assigned to one of three arms, all of which included maintenance lenalidomide:

1. Auto/RVD (n = 254): melphalan at 200 mg/m² and autologous stem cell transplant plus 4 cycles of RVD consolidation (lenalidomide at 15 mg daily on days 1–14; dexamethasone at 40 mg on days 1, 8, and 15; and bortezomib at 1.3 mg/m² on days 1, 4, 8, and 11 every 21 days) followed by lenalidomide maintenance
2. Auto/Auto (n = 247): tandem melphalan (200 mg/m²) plus transplant followed by lenalidomide maintenance
3. Auto/Maintenance (n = 257): single autotransplant followed by lenalidomide maintenance

No Differences Among Arms

The Data Safety and Monitoring Board allowed early release of the data. At a median follow-up of 38 months, progression-free survival was not significantly improved by the additional interventions. Progression-free survival rates were 56.7% for Auto/RVD, 56.5% for Auto/Auto, and 52.2% for Auto/Maintenance. The corresponding probabilities of overall survival were 85.7%, 82.0%, and 83.4%, Dr. Stadtmauer reported.

By cytogenetic risk group, “high-risk patients did worse than standard-risk patients, but there were no differences by treatment arm,” he reported.

Standard-risk patients had 38-month progression-free survival rates of 59.5%, 60.9%, and 55.9% with Auto/RVD, Auto/Auto, and Auto/Maintenance, respectively. For high-risk patients, these rates were 48.3%, 42.2%, and 40.2%. Approximately 78% of patients with high-risk disease were alive at 38 months, he said, calling this “an impressive result.”

When analyzed according to treatment received—ie, per-protocol—there remained no differences among the arms.

Second malignancies emerged in 39 (5.1%) of the 758 patients, including 15 in the Auto/RVD arm, 14 in the Auto/Auto arm, and 10 in the Auto/Maintenance arm. The most frequently reported second malignancy was leukemia in the Auto/RVD and Auto/Auto arms and solid tumors in the Auto/Maintenance arm. The cumulative incidence of a new malignancy in the first 38 months was 6.0% for Auto/RVD, 5.9% for Auto/Auto, and 4.0% for Auto/Maintenance therapy.

The emergence of many new treatments for multiple myeloma opens the door for evaluating enhanced treatment approaches that might be more effective, Dr. Stadtmauer said, commenting, “I believe that the results of this study suggest it would be reasonable to compare any new treatments to the standard therapy of melphalan followed by a single autotransplant followed by lenalidomide maintenance.”

The final analysis will be performed after all patients have been followed for at least 38 months. A long-term follow-up trial to track outcomes in these patients is ongoing. ■

Disclosure: Dr. Stadtmauer has consulted for Amgen, Takeda, Celgene, Novartis, and Janssen.

Reference

1. Stadtmauer EA, et al: Comparison of autologous hematopoietic cell transplant (autoHCT), bortezomib, lenalidomide and dexamethasone consolidation with lenalidomide maintenance, tandem autoHCT with lenalidomide maintenance and autoHCT with lenalidomide maintenance for up-front treatment of patients with multiple myeloma. 2016 ASH Annual Meeting. Abstract LBA-1. Presented December 6, 2016.