Stem Cell Transplant Continues to Show Benefit in 'Novel-Agent Era' of Multiple Myeloma

Author(s):

Early findings from a phase III clinical trial suggest that patients with multiple myeloma who receive upfront autologous stem cell transplant survive longer without disease progression than those who receive chemotherapy alone.

Michele Cavo, MD

Early findings from a phase III clinical trial suggest that patients with multiple myeloma who receive upfront autologous stem cell transplant (ASCT) survive longer without disease progression than those who receive chemotherapy alone, according to findings presented ahead of the 2016 ASCO Annual Meeting.

“For the past 10 to 15 years, therapies with novel non-cytotoxic drugs have increased the response rate and significantly improved survival in previously untreated patients. The remarkable activity of novel therapies has recently questioned the role of upfront ASCT for patients with multiple myeloma,” said lead study author Michele Cavo, MD, head of the Seràgnoli Institute of Hematology at the University of Bologna School of Medicine. “However, our findings show that upfront, high dose chemotherapy and ASCT continues to be the best treatment option for fit patients with newly diagnosed multiple myeloma even in the novel-agent era.”

The large prospective, multicenter, intergroup, randomized phase III study, which was conducted by the European Myeloma Network (EMN), included 1266 patients who were newly diagnosed with multiple myeloma. Following induction therapy with bortezomib-cyclophosphamide-dexamethasone (VCD) patients were randomly assigned to receive either bortezomib-melphalan-prednisone (VMP) or high dose melphalan followed by single ASCT. In treatment centers with a standard policy of performing two ASCTs, patients were randomly assigned to either VMP with single or double ASCT.

In the second stage of the study, patients in both groups were randomized to receive a bortezomib-based consolidation therapy or no consolidation therapy. Finally, all patients received lenalidomide maintenance until progression or intolerable toxicity.

The primary endpoint of the study was the probability of surviving without progression of the disease starting from the first randomization. The first prespecified interim analysis was performed in January 2016.

After a median follow-up of 23.9 months, median progression-free survival (PFS) was not yet reached, but data showed that patients who received ASCT progressed more slowly than those who received VMP therapy without transplant, said Cavo.

Among patients that had not yet experienced disease progression, those randomized to upfront ASCT had a 24% reduction in the risk of progressing at any future time point compared with those randomized to chemotherapy alone including bortezomib (HR, 0.76; 95% CI, 0.61-0.94; P = .01). The difference between the two groups was statistically significant, said Cavo.

Certain subgroups of patients experienced an additional benefit with ASCT. Patients with advanced disease according to International Staging System that were randomized to the ASCT arm, had a 48% lower chance of progressing at the next analysis compared to those not receiving transplant (HR, 0.52; 95% CI, 0.32-0.85; P = .01).

Among patients with high-risk cytogenetics including 17p deletion, ASCT was associated with a 28% lower chance of future progression compared to VMP therapy without transplant (HR, 0.72; 95% CI, 0.54-0.97; P = .03).

Those receiving ASCT were also more likely to achieve a high quality response with at least 90% tumor cell mass reduction to treatment compared with patients who did not have a transplant (84% and 74%, respectively). This is an important indicator of longer survival, said Cavo.

“Patients randomized to upfront high dose chemotherapy and ASCT had a significant reduction in the risk of progression or death compared to those receiving only chemotherapy, including the novel agent bortezomib,” said Cavo. “The superior efficacy of high dose chemotherapy and ASCT over chemotherapy including bortezomib is further supported by the significant enhanced probability of achieving a high quality response.”

For patients at a low risk of relapse, a longer follow-up is required to carefully compare the different arms of the study. Interim analysis of data related to the second randomization to consolidation therapy or no consolidation therapy is not yet complete. The study is ongoing, and future analyses will assess overall survival, toxicity and quality of life as well as other measures.

The FDA approved bortezomib for the treatment of patients with multiple myeloma in 2008 based on an international, multicenter, open label, active-control trial in previously untreated patients with symptomatic multiple myeloma. HDM with ASCT has been traditionally considered the standard of care for younger and fit patients with newly diagnosed multiple myeloma.

Palumbo A, Zweegman S, Dimopoulos M, et al. Upfront autologous stem cell transplantation (ASCT) versus novel agent-based therapy for multiple myeloma (MM): a randomized phase 3 study of the European Myeloma Network (EMN02/HO95 MM trial). J Clin Oncol. 2016 (suppl; abstr 8000).