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Myeloma at 2016 Hematology Meeting
A Banner Year for Myeloma at the 2016 Hematology Meeting

Released: December 27, 2016

Expiration: December 26, 2017

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The 2016 ASH Annual Meeting was another banner year for myeloma treatment, with presentations of practice-changing studies, updates of important trials presented in previous years, and early glimpses of exciting advances in the making.

Transplantation
The results of the phase III IFM 2009 trial presented at the 2015 ASH meeting highlighted the continuing role of single autologous stem cell transplant (ASCT) as consolidation therapy after induction therapy (significant reduction in risk of progression vs no transplant). However, the role of a tandem ASCT and post-ASCT consolidation therapy continue to be debated. Results from 2 large phase III trials presented at the 2016 ASH meeting sought to provide clarity on these questions, but results were mixed.

The STaMINA trial (N = 758) randomized patients with newly diagnosed myeloma who had already received induction therapy and a single ASCT to an additional (tandem) transplant or brief consolidation with VRd, both followed by lenalidomide maintenance until progression. A third arm received no consolidation or second transplant and proceeded directly to lenalidomide maintenance after the initial ASCT. Results showed no additional benefit for post-ASCT consolidation or tandem ASCT, with similar PFS and OS after 38 months. By contrast, patients enrolled on the European Myeloma Network EMN02 trial (N = 1510) received induction treatment with VCd, followed by randomization to consolidation with VMP or ASCT (single or tandem). Further randomization to either 2 cycles of VRd consolidation or no consolidation was also performed. All patients then received lenalidomide maintenance until progression. Results from this second trial demonstrated a PFS advantage for both a tandem ASCT as well as for use of VRd consolidation.

There are several critical differences between these studies that make it difficult to draw strong conclusions. First, both studies have relatively short follow-up, but as the data mature, a clearer picture may emerge. The STaMINA trial enrolled patients in the United States who had already received a variety of induction regimens, and a nearly one third of the patients assigned to the tandem arm did not receive a tandem SCT. The European EMN02 study used VCd induction therapy, whereas in the US STaMINA trial, more than 50% of patients received VRd induction. Based on these 2 studies, it is reasonable to assume that post-ASCT consolidation or tandem ASCT is unnecessary for the average patient with myeloma who has responded to an effective triplet induction regimen followed by maintenance therapy. However, the trend seen in the EMN02 data, as well as the results of a previous analysis of combined European data, suggest that tandem ASCT may have a role in patients with myeloma and high-risk cytogenetics.

Daratumumab
Daratumumab is a recently approved anti-CD38 antibody, and several interesting updates were presented from phase III studies in myeloma. For the first time, a systematic assessment was made of minimal residual disease (MRD) testing in phase III trials in the relapsed setting. Results showed high rates of MRD-negative responses with daratumumab combined with either lenalidomide/dexamethasone (POLLUX) or bortezomib/dexamethasone (CASTOR). In POLLUX, the MRD rate was as high as 31.8% with daratumumab vs 8.8% with lenalidomide/dexamethasone alone. Likewise, the MRD rate in CASTOR was as high as 18.3% vs 3.6%, respectively. Of note, regardless of treatment, patients who achieved MRD negativity had 1-year PFS rates of > 90%. These results highlight the significant benefit of targeting CD38 in the treatment of relapsed myeloma. Of importance, all patients experienced significant benefit regardless of the number of previous therapies they had received, highlighting the important role of daratumumab in the management of patients with early relapse. In addition, early data on the SC administration of daratumumab was also quite promising and may allow for easier administration by shortening the infusion time vs IV administration. This will increase patient convenience without any increase in the associated adverse events of this agent.

Promising New Agents: Venetoclax and Selinexor
Finally, promising results from early trials of several new agents were also presented. Venetoclax, a selective inhibitor of BCL-2, produced responses in a phase I study in nearly 40% of patients with relapsed/refractory myeloma, particularly those with t(11;14) translocations. These initial results suggest that the subgroup of patients with t(11;14) and a favorable (high) BCL2/BCL2L1 gene expression ratio may achieve a higher response rate. In a phase Ib study, combining venetoclax with bortezomib led to responses in nearly 80% of patients with 1-3 previous lines of therapy, far higher than what would have been expected with bortezomib and dexamethasone in this setting.

In the phase II STORM trial, selinexor, a first-in-class selective inhibitor of nuclear export (SINE) protein exportin 1 (XPO1) in combination with dexamethasone, produced a 20% response rate among patients who were “quad refractory” to lenalidomide, pomalidomide, bortezomib, and carfilzomib, as well as in those also refractory to daratumumab (“penta refractory”). In the phase Ib STOMP trial of selinexor in combination with bortezomib/dexamethasone in patients with refractory myeloma, the ORR was 77%, including 27% with at least a very good PR. Likewise, in a phase I MMRC trial in relapsed/refractory myeloma, the combination of selinexor, carfilzomib, and dexamethasone produced an ORR of 75%. These and other selinexor combination regimens are currently in phase II clinical testing for relapsed/refractory myeloma.

How do you see these results influencing your clinical practice? Share your thoughts in the comment box below.

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