TRANSPLANT STILL THE BEST OPTION FOR MYELOMA

With new therapies for multiple myeloma getting ever better, is transplant still necessary? For now, it seems the answer is yes.

Up-front treatment with high-dose chemotherapy and autologous stem cell transplant (ASCT) is the current standard of care for younger, fit patients. Evidence from randomized trials show that ASCT improves survival in comparison with chemotherapy alone. But what about novel targeted therapies?

In the first large trial to compare a targeted therapy regimen based on bortezomib (Velcade, Millennium Pharmaceuticals, Inc) with transplant, up-front ASCT showed a significant reduction in the risk for progression, said lead study author Michele Cavo, MD, head of the Seràgnoli Institute of Hematology at the University of Bologna, Italy.

Dr Cavo was speaking at a press briefing held in advance of the American Society of Clinical Oncology (ASCO) 2016 Annual Meeting in Chicago.

Although median progression-free survival (PFS) has not yet been reached, patients in the ASCT arm had a 24% lower risk for disease progression at any future time point in comparison with those receiving the bortezomib regimen.

"These preliminary results support the up-front use of high-dose chemotherapy and transplantation, and it continues to be the best treatment option for fit patients with newly diagnosed myeloma, even in the era of novel agents," he said.

New Drugs Need Evaluation

It is unlikely that these new results will settle the wider debate of whether transplant is still needed in the era of novel targeted agents, according to Richard Schilsky, MD, ASCO chief medical officer and former chief of the Section of Hematology-Oncology at the University of Chicago.

"This won't settle the issue, mostly because there a whole slew of newer agents that have been introduced since bortezomib that are even more effective, so how those drugs compare to a transplant-based regimen remains to be seen," Dr Schilsky said in an interview.

Bortezomib is a proteasome inhibitor that was approved by the US Food and Drug Administraiton in 2008 for first-line treatment of multiple myeloma. It is now part of standard treatment regimens for patients with newly diagnosed disease, whether or not they are able to undergo ASCT.

But since the approval of bortezomib, four new agents have come on the market. All four were approved in the United States last year:

• Panobinostat (Farydak, Novartis Pharmaceuticals Corporation) was approved February 23, 2015, for patients with relapsed multiple myeloma who have received at least two prior standard therapies, including bortezomib and an immunomodulatory agent.
• Daratumumab (Darzalex, Janssen Pharmaceuticals, Inc), the first monoclonal antibody for use in this disease, was approved November 16, 2015, for patients who have previously received at least three prior treatments.
• Ixazomib (Ninlaro, Takeda Pharmaceutical Company, Ltd) was approved November 20, 2015, for the treatment of multiple myeloma for patients who have received one or more previous therapies.
• Elotuzumab (Empliciti, Bristol-Myers Squibb Company), another monoclonal antibody, was approvedNovember 30, 2015, for use in combination with lenalidomide (Revlimid, Celgene Corporation) and dexamethasone (multiple brands) for patients with multiple myeloma who have previously received one to three other therapies.
  The data that Dr Cavo will present at the meeting come from the European Myeloma Network EMN02/HO95 trial. The study compared four cycles of bortezomib-melphalan-prednisone (VMP) with high-dose melphalan (HDM) and single or double ASCT (limited to centers that use tandem ASCT) as intensification therapy following induction with bortezomib-cyclophosphamide-dexamethasone and subsequent collection of peripheral blood stem cells (designated R1).
  Consolidation therapy with bortezomib-lenalidomide-dexamethasone was then compared with therapy that had no consolidation, followed by lenalidomide maintenance until progression or toxicity in both patient cohorts (designated R2).
  The primary endpoint was PFS in R1. A prespecified interim analysis was performed in January 2016 when at least 33% of the required events had been observed.
  A total of 1266 patients in R1 were randomly assigned to VMP (n = 512) or HDM (n = 754) and were eligible for evaluation.
  The median follow-up period for R1 was 24 months. PFS was significantly better in the HDM arm (HR = 0.76; P = 0.010).
  This PFS benefit was observed across all predefined patient subgroups.
  "The PFS benefit with ASCT was of relevance for patients at risk of early disease," Dr Cavo noted. In particular, he pointed out the subgroup of patients with stage 3 disease (determined in accordance with the revised International Stage System) and patients with high-risk cytogenetic profiles had a relative reduction in the risk for progression or death of 48% and 28%, respectively. He also pointed out that the superiority of ASCT over VMP is further supported by the significant improvement in the rate of very good partial response: 84% vs 74% (HR = 1.90; P < .0001).
  Randomization to HDM (HR = 0.61; P = .001) was confirmed to be an independent predictor of prolonged PFS, according to a Cox regression model.
  Overall survival is not yet mature, and no difference between the treatment groups was evident.
  "For patients at low risk of relapse, a longer follow-up is required to carefully compare the different arms of the study," he said, adding that additional prespecified comparisons, including consolidation vs no consolidation, VMP vs either single or double ASCT, and also single vs double ASCT, will be performed in future analyses.
  Option for Younger Patients
  Approached by Medscape Medical News for an independent comment, Noopur Raje, MD, director, Multiple Myeloma Program at Massachusetts General Hospital, in Boston, reiterated that these new data show that transplantation does result in a PFS benefit.
  "This abstract suggests that this still holds true," said Dr. Raje. "It does not include all of the new drugs, but I think more and more data suggest that at least in the younger patients, transplant has to continue to be viewed as an option."
  She also pointed out that although ASCT does increase PFS, it does not seem to affect overall survival. "So you can say that if overall survival doesn't matter, does one need to have a transplant?"
  Research has also shown that minimal residual disease (MRD) plays a role in outcomes. "Data presented at ASH last year showed that if you become MRD negative, the outcome is better, and that was not surprising," Dr Raje explained. "Whether you got a transplant or not, if you became MRD negative, you did better than those who did not, the point here being, it doesn't really matter how you got to the MRD-negative status, whether with transplant or not. The outcome should be better," she continued. "We don't have the kind of data that speaks to that, but that is a secondary conclusion.
  "So for younger patients, transplant is here to stay for now," Dr Raje added. "But once we start using MRD as a study endpoint, we may be able to pinpoint those patients who absolutely should have a transplant, but we don't have those data yet."
  The study received funding from the HOVON Foundation. Several coauthors have disclosed financial relationships with industry, as noted in the abstract.
  American Society of Clinical Oncology (ASCO) 2015 Annual Meeting: Abstract 8000, to be presented June 3, 2016.