Dual Transplant Prevails in Patients With Newly Diagnosed Myeloma

Michele Cavo, MD

Patients with newly diagnosed multiple myeloma had significant improvement in progression-free survival (PFS) when treated with dual versus single autologous stem-cell transplant (ASCT), preliminary results of a randomized trial showed.

After a median follow-up of 32 months, patients assigned to a double transplant had a 3-year PFS of 74%, whereas those who underwent a single transplant had a 3-year PFS of 62%. The median PFS had yet to be reached in either group.

Patients with high-risk cytogenetics and other poor-prognosis features appeared to derive the greatest benefit from dual ASCT, Michele Cavo, MD, reported at the American Society of Hematology meeting in San Diego.

“The results should be cautiously interpreted, due to the immature follow-up and a possible power limitation of the study,” said Cavo, a professor at Seràgnoli Institute of Hematology in Bologna, Italy. “Preliminary data reported herein may support the benefits of double autologous stem cell transplant in poor-prognosis patients and, in particular, in the subgroup of those who carry high-risk cytogenetic abnormalities.”

“Mature analysis of the study is needed before formal conclusions can be drawn,” he added.

The role of dual transplant in younger and healthier patients with newly diagnosed multiple myeloma remains controversial. Phase III trials conducted during the 1990s yielded conflicting results. None of the trials were conducted during the era of novel agents for myeloma, Cavo said.

A recent integrated analysis of 4 European trials employed patient-level data from comparisons of bortezomib-based and nonbortezomib-based ASCT. Limited to patients who were randomized to bortezomib, the analysis showed that dual ASCT provided the greatest benefit over single ASCT among patients with t(4;14) and del(17p) abnormalities and those patients who did not achieve a complete remission with bortezomib-based induction therapy.¹

The National Comprehensive Cancer Network (NCCN) guidelines include tandem ASCT as an option for patients who do not achieve at least a very good partial response to an initial ASCT, Cavo continued. The International Myeloma Working Group recommends double ASCT for patients with high-risk cytogenetics.^2,3

Investigators in the European Myeloma Network continued the evaluation of double ASCT in a randomized trial of patients with newly diagnosed myeloma. Patients initially were randomized to bortezomib-based intensification therapy or to high-dose melphalan induction followed by single or double transplant. Patients were further randomized to bortezomib-based maintenance therapy or no maintenance.

Cavo reported findings from the comparison of single and double ASCT. The transplant comparison included 695 patients, all of whom received 1 or 2 cycles of high-dose melphalan prior to transplant, and lenalidomide maintenance afterward until disease progression. Patients randomized to dual transplant completed the second procedure within 60 days of the first.

The comparison of PFS between patients randomized to single or double transplant was a secondary objective of the overall trial. A prespecified interim analysis was performed after a median follow-up of 31.6 months in the overall trial, and a median follow-up of 27 months in the comparison of single and double transplant as of July 1, 2016.

The analysis included 415 of the 695 randomized patients. The patients had a median age of about 58. The 2 groups did not differ significantly with respect to key demographic or clinical variables.

The median PFS had yet to be reached, but analysis of 3-year PFS showed a significant advantage for dual transplantation (72.7% vs 60.1%). Cavo reported updated findings from a median follow-up of 32 months.

Median PFS still had not been reached in the updated analysis. However, 3-year PFS continued to favor dual transplant: 73.6% versus 62.2%. The 11.4% absolute difference translated into a 30% reduction in the hazard for progression or death (95% CI, 0.49-1.01; P = .05).

Subgroup analysis showed that a consistent advantage favoring dual transplant, including statistically significant differences for patients with high-risk cytogenetics (HR .487; P = .46, baseline lactate dehydrogenase in the upper limit (HR .509; P = .030), revised International Staging System II (HR .539; P = .007), and age >55 (HR .630; P = .048).

Patients with high-risk cytogenetics had a median PFS of 46.8 months with dual transplant, and 26.5 months with a single transplant. The 3-year PFS was 64.9% and 41.4%, respectively (HR .49; P = .046).

Cox regression analysis identified randomization to dual transplant as the only significant predictor of PFS (HR .646; P = .032).

References

1. Cavo M, Salwender H, Rosiñol L, et al. Double vs single autologous stem cell transplantation after bortezomib-based induction regimens for multiple myeloma: an integrated analysis of patient-level data from phase European III studies. Blood. 2013;122(21):767.
2. Kenneth AC, Alsina M, Atanackovic D, et al. Multiple Myeloma, Version 2.2016: Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2015;13(11):1398-1435.
3. Sonneveld P, Avet-Loiseau H, Lonial S, et al. Treatment of multiple myeloma with high-risk cytogenetics: a consensus of the International Myeloma Working Group. Blood. 2016;127(24):2955-2962. doi: 10.1182/blood-2016-01-631200.
4. Cavo M, Beksac M, Dimopoulos M, et al. Intensification therapy with bortezomib-melphalan-prednisone versus autologous stem cell transplantation for newly diagnosed multiple myeloma: an intergroup, multicenter, phase III study of the European Myeloma Network (EMN02/HO95 MM Trial). Presented at: ASH 58th Annual Meeting; December 5, 2016; San Diego, CA. Abstract 673.