Professor and Chair
Department of Hematology and Medical Oncology
Chief Medical Officer
Winship Cancer Institute of Emory University
Sagar Lonial, MD, has disclosed that he has received consulting fees from Amgen, Bristol-Myers Squibb, Celgene, GlaxoSmithKline, Janssen, Novartis, and Takeda Oncology.
As myeloma therapy continues to develop and evolve, the ability to take existing phase III clinical trial data and extrapolate to current treatment paradigms becomes more challenging. One example is the widespread use of post-transplant maintenance therapy. With the broad use of lenalidomide as maintenance therapy and lenalidomide combinations for high-risk patients, how to best approach managing the treatment of patients with early-relapse myeloma is more difficult.
Many phase III trials in patients with early-relapse myeloma are based on lenalidomide/dexamethasone as the backbone of therapy, and the control arm is lenalidomide/dexamethasone alone. Most of these trials had limited enrollment of patients progressing on lenalidomide maintenance therapy; therefore, the results of these pivotal trials (ELOQUENT-2, ASPIRE, TOURMALINE and POLLUX) do not offer the same level of evidence needed to make decisions in the clinical setting of early relapse. While there are trials that use bortezomib/dexamethasone as the control arm, the number is limited. (CASTOR, PANORAMA, and ENDEAVOR)
With the increasing need to use pomalidomide-based salvage therapy in early relapse, there have been no phase III trials using pomalidomide/dexamethasone as the control arm or backbone therapy. The only large data series using pomalidomide as salvage therapy was from the EQUULEUS trial, a large phase II study in which patients were treated with pomalidomide/daratumumab/dexamethasone; however, most were not classified as early relapse.
The OPTIMISMM Trial
This highlights the importance of the OPTIMISMM trial, a randomized, phase III trial comparing the use of bortezomib/dexamethasone (Vd) vs pomalidomide/bortezomib/dexamethasone (PVd) for patients with relapsed myeloma and 1 to 3 prior lines of therapy. In this trial, 559 patients were randomized to 1 of the 2 treatment arms, with induction and then maintenance schedules after 8 cycles of twice-a-week bortezomib administration. The primary endpoint was PFS, and while all patients were exposed to lenalidomide, approximately 69% of patients in each arm were lenalidomide resistant.
Study results showed PFS significantly increased in the PVd arm vs Vd alone (11.2 vs 7.1 months; P < .0001), and when patients with only one previous line of therapy were analyzed, the difference in PFS was even greater for PVd vs Vd (20.7 months vs 11.6 months; P = .0026). Regarding AEs, the frequency of neutropenia and infections was higher in the PVd arm compared with the bortezomib/dexamethasone arm (41.7% vs 8.5% and 30.9% vs 17.8%, respectively). Incidence of peripheral neuropathy was relatively low (8.3% vs 4.4%, respectively).
The true value of this trial is that we finally have phase III data evaluating the benefit of pomalidomide/dexamethasone in early relapse. These data allow us to switch from lenalidomide to pomalidomide in the early-relapse phase and combine it as part of a triplet-based salvage therapy. As clinicians sort through the available data in the management of early-relapse myeloma, the ability to give pomalidomide-based salvage therapy offers many potential advantages, including ease of administration, familiarity with class of agents, and low risk of neuropathy. The OPTIMISMM trial provides a significant data set in a randomized setting that offers baseline data on pomalidomide/dexamethasone in early relapse with anticipated PFS data, as well as the new triplet PVd regimen.
What are your thoughts on the use of pomalidomide in early-relapse myeloma? Let us know in the comments below!