Expert: Don't Abandon Use of ASCT for Myeloma in 'Novel-Agent Era'

Michele Cavo, MD

Although several new agents have shown a benefit in multiple myeloma, upfront autologous stem cell transplant (ASCT) should still be the standard of care for newly diagnosed, young, fit patients, according to Michele Cavo, MD.

“ASCT should not be abandoned in this novel agent era,” says Cavo, head of the Seràgnoli Institute of Hematology at the University of Bologna School of Medicine. “It continues to play a role for these patients.”

Cavo was the lead investigator of the large, prospective, multicenter, intergroup, randomized phase III European Myeloma Network EMN02/HO95 MM trial, preliminary results of which were presented at the 2016 ASCO Annual Meeting.

The study included 1266 patients with newly diagnosed multiple myeloma who received induction therapy with the triplet regimen of bortezomib (Velcade), cyclophosphamide, and dexamethasone (VCD) and then were randomly assigned to receive bortezomib, melphalan, and prednisone (VMP) or high-dose melphalan followed by single ASCT. In treatment centers with a standard policy of performing 2 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. All patients received lenalidomide (Revlimid) maintenance therapy 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.

OncLive: What were the most significant findings from this trial?

In an interview with OncLive, Cavo provides a deeper insight on the study’s findings, as well as the evolving role of ASCT. She also shares other exciting studies on the horizon in multiple myeloma.Cavo: This was the first interim analysis of a large phase III trial conducted by the European Myeloma Network. It was aimed at comparing upfront ASCT—either single or double—versus chemotherapy alone including bortezomib. For this purpose, the regimen VMP was chosen as the reference treatment.

At the time the analysis was performed, the median follow-up was 26 months. Median progression-free survival (PFS) was not yet reached for patients randomized to upfront ASCT. It was 44 months for patients randomized to standard dose intensification therapy with VMP.

The difference between the 2 arms was statistically significant. PFS benefit with upfront ASCT compared with conventional VMP intensification therapy was retained across certain subgroups of patients at low and high risk, including patients with low-risk and high-risk cytogenetic profiles. In both of these risk subgroups, randomization to autologous transplant was associated with a 30% relative reduction in the risk of progression or death compared with VMP. In a multivariate Cox regression analysis, randomization to autologous transplant was an independent variable associated with prolonged PFS.

Does upfront ASCT have any role for older patients?

What was the purpose of conducting this study?

What results of other studies in multiple myeloma do you find to be practice-changing?

Although these results are related to a preliminary interim analysis, these data support the conclusion that upfront ASCT still continues to be a reference therapy for young and fit patients with newly diagnosed multiple myeloma, even in the novel-agent era.In this trial, the upper agent limit was 65. However, in daily clinical practice, patients in the range of 66 to 70, or even higher with no comorbidities, routinely receive ASCT without any risk of early mortality. For patients who are not eligible to receive ASCT, treatment options are continuously expanding.The study was performed in the novel-agent era, and there is a need to compare ASCT with novel agents. This is related to the high level of activity of novel agents introduced into the therapeutic armamentarium for multiple myeloma, which have led to increased rates of complete responses that rival what we have seen with conventional chemotherapy and ASCT.There were data presented at the 2016 ASCO Annual Meeting that confirmed the value of lenalidomide maintenance therapy for patients receiving ASCT. The results were related to a large analysis that included a lot of patients, and the results did support the benefit of continuous lenalidomide maintenance therapy in terms of extended overall survival after ASCT.

Another important study summarized the combination of cyclophosphamide and dexamethasone with ixazomib (Ninlaro). Ixazomib is a next-generation proteasome inhibitor that has the advantage of being orally available. Therefore, the combination of cyclophosphamide and dexamethasone with ixazomib is not only effective in newly diagnosed patients, but is an oral treatment, too.

There were also interesting data regarding the possibility of combining the novel agents for the treatment of relapsed/refractory patients with myeloma.

Reference

Cavo, M Palumbo A, Zweegman S, 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).