NEW YORK—For patients with multiple myeloma who achieve a very good partial response (VGPR) or better after autologous stem cell transplant (ASCT), the current trend among clinicians is to use additional therapy for induction, go to transplant, provide consolidation, and then proceed to maintenance with a single drug.
That was the consensus of experts speaking here at a multiple myeloma session at the Great Debates & Updates in Hematologic Malignancies meeting. Among the topics discussed were whether maintenance therapy prolongs survival, whether the choice of maintenance therapy makes a difference, and who should get treatment. The vast majority of the attendees agreed that maintenance with a single agent, rather than with a doublet regimen or observation alone was the proper way to manage patients in the post-transplant setting.
Sagar Lonial, MD, Professor in the Department of Hematology and Medical Oncology at Emory University School of Medicine, presented evidence on single-agent maintenance: “There are survival benefits in large, randomized trials that support the use of maintenance therapy, and there are also differences between maintenance versus salvage therapy in the duration of response,” he said.
He defined the elements of effective maintenance as a well-tolerated treatment that reduces the depth of disease, helps all biologic subsets of disease, and increases overall survival (OS). “Patients with high-risk disease are known to achieve complete responses [CRs], but the responses are not durable and patients' progression-free survival [PFS] is short in the absence of ongoing therapy. Patients with standard-risk disease—hyperdiploid, low ISS stage—will likely do well, and maintenance may reduce tumor burden and further improve PFS and OS,” he said.
“In standard-risk disease patients, if maintenance can improve OS, you have made a major step forward.”
Multiple options are available as single-agent maintenance, Lonial continued. “Data on steroids from SWOG trials are not convincing, so this is not a good option. Thalidomide toxicity precludes its long-term use, but in the right subset of patients post-transplant, thalidomide maintenance may derive a good benefit more than in the salvage setting. Bortezomib has attractive single-agent activity, but the optimal dose and schedule are unknown. Lenalidomide use with or without steroids is still questioned relating to dose, schedule, and corticosteroid use.”
He focused his discussion on lenalidomide and bortezomib, noting that both the IFM (French Francophone Myeloma Intergroup) and Cancer and Leukemia Group B (CALGB) trials show a PFS benefit of almost 20 months with low-dose lenalidomide alone (with no dexamethasone) as maintenance therapy compared with placebo.
“The initial reports from the IFM trial showed no difference in OS. Now there are hints that longer duration of maintenance makes a difference and does improve survival,” he said.
In the CALGB trial, there was also an improvement in PFS of about 20 months. “Longer follow-up shows that despite crossover the difference holds up, with a survival benefit for the lenalidomide group versus the placebo group,” he said, adding that the most significant risk is for disease progression and the overwhelming issue is death due to progression.
“In both the IFM and CALGB trials, lenalidomide may be effective in the maintenance setting, particularly in low doses,” he said. “Maintenance therapy does improve OS. We have seen the benefit in long, randomized trials that support the use of maintenance therapy. Overall survival should be the endpoint.”
As for bortezomib, he highlighted the HOVON trial that showed improvements in OS for the group who received bortezomib induction and maintenance. “This is not just a PFS benefit. The use of bortezomib in the maintenance setting has a major impact,” he said.
In conclusion, Lonial said, “Maintenance therapy with either bortezomib or lenalidomide improves outcomes of PFS in all trials and OS in two out of three trials, and should be considered a standard. The use of maintenance may allow for lower dosing and fewer adverse events.”
Maintenance with either lenalidomide or bortezomib can be augmented with steroids or combinations in the event of disease progression, he added.
According to the onsite polling, while most of the audience agreed that single-agent maintenance was the preferred therapy, about one in six thought observation only was still called for after listening to the presentation by Tomer Mark, MD, Assistant Professor of Medicine at Weill Cornell Medical College.
He began his talk by giving his definition of maintenance in the post-transplant setting—i.e., any treatment taken after consolidation therapy with the intent of prolongation of duration of response, along with, it is hoped, an increased in survival. “Schedule and dose intensity make this more tolerable than induction chemotherapy,” he said. “We need to focus on the balance between clinical benefit of continuous treatment versus a patient's quality of life.”
The goal of maintenance is to keep the tumor volume down so there is no relapse or retreatment. “As we continue to treat the patient and the tumor burden goes down, we hope to achieve a functional cure for myeloma with continuous treatment,” he said. “That definition of treatment is maintenance. The ultimate goal is improved survival.”
The potential drawbacks of maintenance are the unnecessary exposure to chemotherapy, which can lead to side effects, increased costs, and potential secondary malignancies. “If you burn bridges by generating more resistant clones, you can no longer recycle agents,” Mark said. “The way to induce resistance is to give continuous chemotherapy. We may raise resistant clones on maintenance.”
Many maintenance strategies have been tested post-ASCT, he continued. “The theme is improved CR, but not OS. There is no significant benefit in OS. The lessons from thalidomide maintenance show an increase in PFS, but not OS, in patients who achieve VGPR.”
The data suggest that the overall improvements in progression-free and overall survival are due to improved responses for patients with a significant tumor burden after ASCT, he said, adding that in patients with very good partial responses or better, thalidomide maintenance leads to shorter OS, and salvage therapies don't work as well after thalidomide maintenance.
Results from clinical trials show that lenalidomide leads to an increase in PFS, but not OS in patients who achieve VGPR. Responses deepen, suggesting a consolidation effect of lenalidomide, he explained, adding that there are also more secondary primary malignancies with use of lenalidomide.
In the HOVON trial, bortezomib treatments upgraded the response to 11 to 12 percent of patients achieving a complete response, but there was no statistically significant improvement in OS.
In conclusion, Mark said, “there is no proven benefit for patients who reach VGPR/CR across multiple trials of thalidomide and lenalidomide maintenance after ASCT. No conclusions about bortezomib can be made yet.”
He noted that thalidomide, lenalidomide, and bortezomib maintenance appear to consolidate and deepen responses in patients who achieve less than a VGPR.
Maintenance with a Doublet Regimen
The third speaker at the session, David H. Vesole, MD, PhD, Co-chief and Director of Research at John Theurer Cancer Center at Hackensack University Medical Center in New Jersey, had the more difficult task of supporting the use of a doublet regimen in maintenance. He said that maintenance therapies “are not benign treatments. They have some secondary toxicities,” pointing out that about 12 percent of patients dropped out of the CALGB trial due to toxicity, as did 22 percent of those in the IFM trial.
According to NCCN guidelines, the recommended maintenance therapies for this group of patients includes thalidomide in Category 1; lenalidomide or bortezomib in Category 2A; and interferon, steroids, or thalidomide/prednisone in Category 2B.
Vesole also referenced the results of the IFM and CALGB trials of lenalidomide maintenance after ASCT: “Both trials show that lenalidomide maintenance improves PFS, and the CALGB trial suggests a survival benefit with a 90 percent two-year OS for lenalidomide maintenance versus 83 percent for placebo. Neither of these studies addressed questions regarding duration of therapy, benefit of patients in CR after ASCT, early versus late intervention, or issues related to the depth of CR.”
There is evidence of improved post-transplant response using maintenance with the thalidomide-plus-prednisone doublet, he said. Starting doses of thalidomide at 100 mg plus prednisone at 50 mg improve the three-year PFS, but not OS, he said.
There is also a trend towards improvement in consolidation followed by maintenance, he said. One trial showed a role for consolidation after response with lenalidomide or lenalidomide with corticosteroids after transplantation. Another study combined bortezomib with thalidomide and “got more oomph with consolidation therapy,” including an improvement in PFS, but no survival difference.
The University of Arizona Total Therapy trials also show an improved depth of response after consolidation, even before maintenance.
In summary, Vesole said, “use of thalidomide plus corticosteroids is superior to observation for PFS. There are no data with more modern novel agents as doublets for maintenance. Consolidation with triplets improves the response rate, but there are no data on PFS or OS.”
In the post-debate survey, most of the attendees maintained their positions, with three-quarters supporting maintenance with one agent and 10 percent supporting a doublet regimen. However, a large group of earlier undecided voters switched to observation, so Tomer Mark's arguments can be considered the most persuasive.